Updated Evaluation of the Safety, Efficacy and Tolerability of Pirfenidone in the Treatment of Idiopathic Pulmonary Fibrosis

Figures & data

Table 1 Efficacy, Side Effects and Tolerability of Pirfenidone

Author, Follow-Up Period	Country (No. of Patients)	Baseline Characteristics	Efficacy End-Point(s)	Total Adverse Events, n (%)	Gastrointestinal Side Effects, n (%)	Skin Side Effects, n (%)	Treatment Discontinuation Rate, n (%)
Wijsenbeek^Citation43	Netherlands (52)	Age,yrs: 63.4±7.7 Baseline FVC%: 68.3±18.4	Stable lung function in 17 out of 20 patients treated for >6 months. Decreased cough score in 11 out of 19 patients.	NA	NA	NA	10 (19%)
Ravaglia^Citation44 2008–2013	Italy (81)	Age,yrs (range): 69 (41–81) Baseline FVC%: 70.8 Baseline DLCO%: 41.39	Stable or significantly improved lung function in 59% patients	NA	NA	NA	13 (16%)
Bonella,^Citation45 2006–2012	Germany (45)	Age,yrs: 69±7 Baseline FVC%: 61±15	Stable lung function in 70% patients	NA	17 (38%)	17 (38%)	6 (13%)
Okuda^Citation42 2008–2011	Japan (76)	Age,yrs: 70.5±8.3 Baseline FVC %: 65.3±16.1	Safety of pirfenidone	64 (84.2%)	18 (23.6%)	14 (18%)	14 (18%)
Arai,^Citation46 2009–2011	Japan (41)	Age,yrs(Range): 70 (65–75) Baseline FVC%: 66.7 (54.8–77.8)	Significant reduction in FVC decline in patients with severity grades I–II^$	31 (75.6%)	24 (58.5%)	7 (17%)	2 (15%)
Oltmann^Citation47 2011–2013	Germany (63)	Age,yrs: 68±7 Baseline FVC%: 70±19 Baseline DLCO%: 40± 14	Stable lung function in 62% of Patients, non -statistically significant trend in reduction in FVC decline	52(85%)	36 (59%)	17(28%)	28(46%)
Chaudhuri^Citation48 2011–2013	United Kingdom (40)	Age,yrs (range): 65.8(40–80) Baseline FVC%(range): 77 (46–146) Baseline DLCO%(range): 42.4(14–81%)	Reduction in FVC and DLCO decline at 9 months	40 (58%)	83(46%)	4(10%)	6(15%)
Barratt^Citation41 2012–2017	United Kingdom (115)	Age,yrs: 73.1±8 Baseline FVC%: 74.2±16.2	Tolerability of pirfenidone	66 (57%)	18 (15.6%)	11 (8.5%)	46 (40%)
Hanta^Citation49 2017	Turkey (60)	Age,yrs (range): 67.5(44–90) Baseline FVC%: 68.4±14.35 Baseline DLCO%: 48.7±18	77% patients had stable FVC over 6 months	33 (55%)	21 (35%)	8(13.3%)	1(1.7%)
Yoon^Citation50 2010–2015	South Korea (138)	Age,yrs: 68±7.4 Baseline FVC%: 59.4±14.8 Baseline DLCO%: 45(15)	Rate of disease progression^^ was reduced after treatment (42.9 vs 4.5%, p = 0.008)	118(85.8%)	93 (68%)	43 (31%)	36.4(43%)
Tzouvelekis 2011–2013^Citation51	Greece (43)	Age,yrs: 66.3±9.7 Baseline FVC% : 63.8±20.3	Reduction in FVC decline in 6 months after treatment as compared to before treatment initiation, however this difference was not maintained at 1 year of treatment	NA	15 (34.9%)	8 (18.6%)	9 (20.9%)
Margaritopoulos^Citation52 2011–2016	Greece (90)	Age,yrs: 74.9±11 Baseline FVC%: 81±19.5% Baseline DLCO%: 54.4±17	Mortality reduction in pirfenidone treated cohort when compared to a matched historical cohort of 212 patients. HR 0.40, CI^ 0.21–0.75, p<0.005	NA	30 (33.3%)	17 (18%)	3 (3.3%)
Salih^Citation53 2011–2014	Denmark (113)	Age,yrs: 69.6±8.1 Baseline FVC%: 62.7%±12.1 Baseline DLCO%: 45.1±13.8	The annual decline in FVC% was 3.6±1%. The annual decline in DLCO% from baseline was 2.2±8%	NA	50 (44.2%)	37(32.7%)	18 (16%)

Notes: $ is defined by the Japanese Respiratory Society ; ^ >10% decline in FVC for 6 months.

Abbreviations: FVC, forced vital capacity; DLCO, diffusion capacity.

Table 2 Adverse Drug Reactions in Phase III Trials

Side Effect	CAPACITY 004/006 Trials^Citation5		ASCEND Trial^Citation6
	Pirfenidone (n=345)	Placebo (n=347)	Pirfenidone (n= 278)	Placebo (n=277)
Nausea	125 (36%)	60 (17%)	100 (36%)	37 (13.4%)
Dyspepsia	66 (19%)	26 (7%)	49 (17.6%)	17 (6.1%)
Dizziness	63 (18%)	35 (10%)	49 (17.6%)	36 (13%)
Vomiting	47 (14%)	15 (4%)	36 (12.9%)	24 (8.7%)
Rash/photosensitivity	153 (44%)	46 (14%)	78 (28.1%)	24 (8.7%)
Anorexia	37 (11%)	13 (4%)	44 (15.8%)	18 (6.5%)
Arthralgia	36 (10%)	24 (7%)	–	–
Weight reduction	28 (8%)	12 (3%)	35 (12.6%)	22 (7.9%)
Insomnia	34 (10%)	23 (7%)	31 (11.2%)	18 (6.5%)
Cough	–	–	70 (25.2%)	82 (29.6%)

Table 3 Prevention and Management of Pirfenidone Related Side Effects

Adverse Event	Prevention and Management
General	Dose reduction/interruptions
Rash	Discontinue until rash resolves and re-start at a slow titration schedule. Permanently discontinue if rash recurs
Photosensitivity	Prevention with continuous skin protection with clothing and SPF-50 sunscreen Treat severe reaction with steroids or silver sulfadiazine Permanently discontinue if an allergic reaction occurs
Transaminitis	If AST and ALT elevations are >3 to ⩽5 ULN without symptoms or hyperbilirubinaemia, reduce the dose or interrupt until values return to normal. If AST and ALT elevations are >3 to ⩽5 ULN and accompanied by hyperbilirubinaemia, permanently discontinue pirfenidone. If AST or ALT are >5 ULN, permanently discontinue pirfenidone
Gastrointestinal	Dose reduction or interruption with a slow titration back to full dose as tolerated Use of PPI Take medication with a substantial meal

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal; PPI, proton pump inhibitors.

Table 4 Pirfenidone Dose Titration Protocol

Pirfenidone Titration Schedule
2-week titration schedule^Citation54
Titration interval	Dosing (Total number of pills per day)
Days 1–7	1 tablet TID (3)
Days 8–14	2 tablets TID (6)
Days > 15	3 tablets TID (9)*
4-week titration schedule^Citation37
Titration interval	Dosing (Total number of pills per day)
Days 1–14	1 tablet TID (3)
Days 15–28	2 tablets TID (6)
Days >29	3 tablets TID (9)*

Note: *Full dose.

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