title: Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials.
abstract: BACKGROUND
  Pirfenidone is an oral antifibrotic agent that has been shown to reduce the decline in lung function in patients with idiopathic pulmonary fibrosis (IPF). We performed an integrated analysis of safety data from five clinical trials evaluating pirfenidone in patients with IPF.
  
  
  METHODS
  All patients treated with pirfenidone in the three multinational Phase 3 studies (CAPACITY (studies 004 and 006), ASCEND (study 016)) and two ongoing open-label studies (study 002 and study 012 (RECAP)) were included in the analysis. Safety outcomes were assessed during the period from the first dose until 28 days after the last dose of study drug.
  
  
  RESULTS
  A total of 1299 patients were included in the analysis. The cumulative total exposure to pirfenidone was 3160 person exposure years (PEY). The median duration of exposure was 1.7 years (range 1 week to 9.9 years), and the mean (±SD) daily dose was 2053.8 (±484.9) mg. Gastrointestinal events (nausea (37.6%), diarrhoea (28.1%), dyspepsia (18.4%), vomiting (15.9%)) and rash (25.0%) were the most common adverse events; these were generally mild to moderate in severity and without significant clinical consequence. Elevations in alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal occurred in 40/1299 (3.1%) patients (adjusted incidence, 2.3 per 100 PEY). Elevations were generally transient and reversible with dose modification or discontinuation.
  
  
  CONCLUSIONS
  A comprehensive analysis of safety outcomes in a large and well-defined cohort of 1299 patients with IPF who were followed prospectively for up to 9.9 years demonstrated that long-term treatment with pirfenidone is safe and generally well tolerated.
  
  
  BACKGROUND
  NCT00287716, NCT00287729, NCT00662038, NCT01366209.
authors.affiliation: Department of Medicine , Vanderbilt University Medical Center , Nashville, Tennessee , USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lancaster
authors.affiliation: Department of Clinical and Biological Sciences , University of Turin , Turin , Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Albera
authors.affiliation: InterMune Inc , Brisbane, California , USA.
authors.forename: Williamson Z
authors.initials: WZ
authors.lastname: Bradford
authors.affiliation: Department of Pneumology and Allergy , Ruhrlandklinik, University of Duisburg-Essen , Essen , Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Costabel
authors.affiliation: Emeritus Professor of Respiratory Medicine , Imperial College , London , UK.
authors.forename: Roland M
authors.initials: RM
authors.lastname: du Bois
authors.affiliation: InterMune Inc , Brisbane, California , USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fagan
authors.affiliation: InterMune Inc , Brisbane, California , USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fishman
authors.affiliation: AIRMED, Alfred Hospital and Monash University , Melbourne, Victoria , Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Glaspole
authors.affiliation: Department of Medicine and Surgery , University of Miami Miller School of Medicine , Miami, Florida , USA.
authors.forename: Marilyn K
authors.initials: MK
authors.lastname: Glassberg
authors.affiliation: Department of Medicine , University of California San Francisco (UCSF) , San Francisco, California , USA.
authors.forename: Talmadge E
authors.initials: TE
authors.lastname: King
authors.affiliation: Department of Medicine , Columbia University Medical Center , New York, New York , USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lederer
authors.affiliation: InterMune Inc , Brisbane, California , USA.
authors.forename: Zhengning
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Lung Transplant Program, Inova Fairfax Hospital , Falls Church, Virginia , USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Nathan
authors.affiliation: Lung Disease Department , Paulista School of Medicine, Federal University of São Paulo , São Paulo, Brazil.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Pereira
authors.affiliation: Department of Medicine , National Jewish Health , Denver, Colorado , USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Swigris
authors.affiliation: Pneumology Service , Assistance Publique-Hôpitaux de Paris, Avicenne University Hospital , Bobigny , France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Valeyre
authors.affiliation: Department of Medicine , Cedars Sinai Medical Center , Los Angeles, California , USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
keywords: Interstitial Fibrosis
references.citation: N Engl J Med. 2014 May 29;370(22):2083-92
references.pmid: 24836312
references.citation: Eur Respir J. 2010 Apr;35(4):821-9
references.pmid: 19996196
references.citation: Lancet. 2011 May 21;377(9779):1760-9
references.pmid: 21571362
references.citation: Pulm Pharmacol Ther. 2009 Aug;22(4):279-85
references.pmid: 19328861
references.citation: Am J Respir Crit Care Med. 2011 Mar 15;183(6):788-824
references.pmid: 21471066
references.citation: Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1061-9
references.pmid: 10194146
references.citation: Am J Respir Crit Care Med. 2005 May 1;171(9):1040-7
references.pmid: 15665326
references.citation: Respirology. 2014 Jul;19(5):740-7
references.pmid: 24836849
references.citation: Sarcoidosis Vasc Diffuse Lung Dis. 2014 Oct 20;31(3):198-205
references.pmid: 25363219