The FDA and Safe Use of Long-Acting Beta-Agonists in the ...

PERSPECTIVEFDA and Safe Use of Long-Acting Beta-Agonistsinhaled corticosteroid alone.Third, long-term use of LABAsin patients with asthma shouldbe limited to those whose asthmacannot be controlled withasthma-controller medications.Finally, the FDA recommendsthe use of combination productscontaining an inhaled corticosteroidand a LABA in childrenand adolescents because of thedifficulty of ensuring compliancewith both medicationswhen they are administered separatelyin these groups.The FDA’s recommendationthat LABA use be discontinued ifpossible after asthma control hasbeen achieved may cause consternationamong prescribers, sinceasthma treatment guidelines andcurrent practice focus on steppingdown the dose of inhaledcorticosteroids in patients whorequire combination cortico steroidand LABA therapy. 5 Theguidelines recommending longtermuse of LABAs were partlyinfluenced by studies showing abenefit from adding a LABA toan inhaled corticosteroid for thelong-term treatment of persistentasthma. These studies haveseveral limitations, however. Forinstance, the benefits shownwere largely a measure of thebeta-agonist effect, such as improvedairflow and reduced rescueuse of SABAs. There are nostudies showing that LABAs(alone or in conjunction with inhaledcorticosteroids) increasesurvival or positively affect severeasthma exacerbations (thosenecessitating intubation or hospital-basedcare). Given the clearbenefits of inhaled corticosteroidsin patients with asthmaand the fact that they have notbeen associated with serious adverseoutcomes, the FDA believesit is prudent to emphasize theiruse and limit the long-term useof LABAs.An important unansweredquestion about LABA use iswhether concomitant use of aninhaled corticosteroid mitigatesthe risk of asthma-related death.The SNS study and SMART didnot systematically test the effectof concomitant use and cannotanswer this question. At the2008 advisory committee meeting,findings from meta-analysesof controlled clinical trialsof LABAs used to treat asthmawere presented by the FDA andthe LABA manufacturers. Someof the analyses suggested a decreasedrisk of serious asthmarelatedadverse events in associationwith combination therapyas compared with a LABA alone,but other analyses did not. Giventhe seriousness of the risksassociated with LABA use andthe uncertainty about the role ofinhaled corticosteroids in mitigatingthis risk, the FDA believesthat long-term use of LABAsshould be limited to patients whotruly need them.The risk of serious asthma exacerbationsand asthma-relateddeath is not unique to LABAs. Ithas been known for over 50years that SABAs can worsenasthma and cause asthma-relateddeath. Although the mechanismsby which beta-agonistbronchodilators cause asthmarelateddeath remain uncertain,it is hypothesized that they mayincrease sensitivity to bronchoconstrictivestimuli or mask thesymptoms of worsening asthma.To minimize this risk, currentasthma-treatment guidelinesrecommend that albuterol andother SABAs be used only asneeded for short-term symptomrelief and that asthma-controllermedications be used to minimizeSABA use. 5 Other than theduration of bronchodilatation,the basic pharmacologic activityand clinical effect of LABAs andSABAs are the same. The FDAtherefore believes it is inconsistentto recommend long-term useof LABAs, particularly since LABAshave also been shown to increasethe risk of asthma-related death.The FDA intends to take severalactions to ensure that prescribersand patients are awareof the new recommendations forthe safe use of LABAs. Under itsSafe Use Initiative, the agencywill work with public and privatehealth care groups to widelydisseminate information aboutthe new labeling. The FDA willalso work with these partners toassess whether prescribing patternschange, leading to the prescribingof LABAs only withconcomitant use of a controllerdrug, compliance with the recommendationof dual LABA andinhaled-corticosteroid therapy, andoverall decreased use of LABAs.Further studies are needed todefinitively determine whether theaddition of LABAs to inhaled corticosteroidsincreases the risk ofserious asthma outcomes. Usingnew authorities under FDAAA,the FDA will require manufacturersof LABAs to conduct largeclinical trials that evaluate thisrisk by comparing inhaled corticosteroidsplus LABAs with inhaledcorticosteroids alone. Theagency will seek input into thedesign of these studies at an openadvisory committee meeting inMarch 2010. Until such data areavailable, the FDA believes that1170n engl j med 362;13 nejm.org april 1, 2010Downloaded from www.nejm.org at UNIVERSITY OF KANSAS MEDICAL CENTER on April 8, 2010 .Copyright © 2010 Massachusetts Medical Society. All rights reserved.

PERSPECTIVEFDA and Safe Use of Long-Acting Beta-Agoniststhe existing evidence supportsthe approaches outlined here.Disclosure forms provided by the authorsare found with the full text of thisarticle at NEJM.org.From the Division of Pulmonary and AllergyProducts, Office of New Drugs (B.A.C.),and the Office of Surveillance and Epidemiology(G.D.P.), Center for Drug Evaluationand Research, Food and Drug Administration,Silver Spring, MD.This article (10.1056/NEJMp1002074) waspublished on February 24, 2010, at NEJM.org.1. DailyMed. Professional drug-label information.Rockville, MD: National Library ofMedicine, 2010. (Accessed February 23,2010, at http://dailymed.nlm.nih.gov/dailymed/about.cfm.)2. Martinez FD. Safety of long-acting betaagonists— an urgent need to clear the air.N Engl J Med 2005;353:2637-9.3. Kramer JM. Balancing the benefits andrisks of inhaled long-acting beta-agonists —the influence of values. N Engl J Med 2009;360:1592-5.4. Drazen JM, O’Byrne PM. Risks of longactingbeta-agonists in achieving asthmacontrol. N Engl J Med 2009;360:1671-2.5. National Asthma Education andPrevention Program. Expert panel report 3:guidelines for the diagnosis and managementof asthma. Bethesda, MD: NationalHeart, Lung, and Blood Institute, August2007. (NIH publication no. 07-4051.)Copyright © 2010 Massachusetts Medical Society.n engl j med 362;13 nejm.org april 1, 20101171Downloaded from www.nejm.org at UNIVERSITY OF KANSAS MEDICAL CENTER on April 8, 2010 .Copyright © 2010 Massachusetts Medical Society. All rights reserved.