Real-World Practice Patterns for Prevention and Management of Potential Adverse Events with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis

Real-World Practice Patterns for Prevention and Management of Potential Adverse Events with... Pulm Ther (2018) 4:103–114 https://doi.org/10.1007/s41030-018-0056-8 ORIGINAL RESEARCH Real-World Practice Patterns for Prevention and Management of Potential Adverse Events with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis . . . . Mark L. Wencel Tmirah Haselkorn Susan L. Limb John L. Stauffer . . Elizabeth Morgenthien Karina Raimundo Peter P. LaCamera Received: February 28, 2018 / Published online: May 29, 2018 The Author(s) 2018 Results: A total of 169 pulmonologists partici- ABSTRACT pated. Gastrointestinal (GI) intolerance was the most important factor in implementing alter- Introduction: Pirfenidone is an oral antifibrotic native titration schedules for pirfenidone. agent approved for idiopathic pulmonary Approximately three-quarters of pulmonolo- fibrosis (IPF). Real-world data on adverse event gists recommended the standard titration (AE) management for pirfenidone are limited. scheme for starting treatment; however, a range Strategies for managing potential antifibrotic of titration schedules up to 8 weeks were therapy AEs were examined in a sample of US described, with a 4-week schedule being most pulmonologists. common. Pulmonologists reported that most Methods: An online, self-administered survey patients treated with alternative titration was fielded to pulmonologists between April 10 schedules could achieve the full dose of pir- and May 17, 2017. Pulmonologists were inclu- fenidone. Pulmonologists who were most ded if they spent [ 20% of their time in direct effective at mitigating pirfenidone-related GI patient care and had C 5 patients with IPF on AEs by advising dosing at mealtimes more fre- antifibrotic therapy. Participants answered quently recommended taking pirfenidone dur- questions regarding initiation of pirfenidone, ing a substantial meal than pulmonologists who dose titration, and management of potential were less effective. For photosensitivity AEs, AEs. pulmonologists recommended sunscreen use, sun avoidance, wearing a hat, and ultraviolet Enhanced digital features To view enhanced digital protection factor clothing. features for this article go to https://doi.org/10.6084/ m9.figshare.6222455. Conclusions: Pulmonologists reported that alternative titration schedules for initiating M. L. Wencel (&) pirfenidone were common and can aid in Via Christi Health, Wichita, KS, USA maintaining the full dose. Proposed strategies to e-mail: mark.wencel@ascension.org ameliorate pirfenidone-related GI and photo- sensitivity AEs included taking pirfenidone T. Haselkorn EpiMetrix, Inc., Los Altos, CA, USA during a substantial meal and minimizing sun exposure, respectively. S. L. Limb  J. L. Stauffer  E. Morgenthien Funding: F. Hoffmann-La Roche Ltd./Genen- K. Raimundo Genentech, Inc., South San Francisco, CA, USA tech, Inc. Plain Language Summary: Plain language P. P. LaCamera summary available for this article. St. Elizabeth’s Medical Center, Boston, MA, USA 104 Pulm Ther (2018) 4:103–114 Keywords: Adverse event management; CAPACITY, pirfenidone reduced the risk of Antifibrotic therapy; Idiopathic pulmonary death at 1 year by 48% compared with placebo fibrosis; Pirfenidone; Real-world; Titration [3, 7]. For patients receiving pirfenidone, gastrointestinal (GI)- and skin-related adverse events (AEs) are the most common AEs reported PLAIN LANGUAGE SUMMARY [3–5, 8]. These AEs can affect tolerability in some patients, particularly within the first Idiopathic pulmonary fibrosis (IPF) is a deadly 6 months of treatment [9]. In the phase III trials, lung disease. Pirfenidone is a medication that the median time to the first GI AE (in 77.8% of slows down the disease in patients with IPF. patients), rash AE (35.8%), and photosensitivity Stomach- and skin-related side effects are com- AE (9.3%) was 14.0 (range, 5.0–40.0), 82.0 mon with pirfenidone. There is little informa- (range, 49.0–132.0), and 90.0 (range, tion on ways to manage these side effects. In an 48.0–149.0) days, respectively [10]. online survey, US pulmonologists (lung disease A 2-week titration period is recommended specialists) answered questions on how they for pirfenidone, with a starting dose of one start patients on pirfenidone, adjust doses, and 267-mg pill (capsule or tablet) three times daily manage side effects. The use of different dosing (tid) with food for 1 week, followed by two pills schedules when starting pirfenidone was com- tid (534 mg) with food for 1 week and then mon practice among these pulmonologists and three pills (801 mg) tid (maintenance dose) with could help patients stay on pirfenidone if they food [6]. Once maintenance dosing is achieved, had side effects. Taking pirfenidone during a patients may continue to take three 267-mg large meal and staying out of the sun were key pills tid or switch to one 801-mg pill tid, which recommendations for managing common reduces the pill burden in patients receiving stomach and skin side effects. pirfenidone [11]. One empirical method for preventing pir- fenidone-related GI AEs is gradual dose titra- INTRODUCTION tion upon initiation of pirfenidone [9]. Although an expert panel has recommended Idiopathic pulmonary fibrosis (IPF) is a pro- strategies for mitigating pirfenidone AEs and gressive, irreversible, and fatal fibrotic lung dis- management strategies have been proposed on ease [1]. The clinical course of IPF is highly the basis of clinical trial data, real-world data variable and unpredictable in individual on AE management in patients receiving pir- patients; the median survival is 2–5 years from fenidone therapy are limited [9, 12]. Other real- diagnosis [2]. IPF typically presents with unex- world data analyses have focused on efficacy plained dyspnea on exertion or cough and tolerability of pirfenidone, physicians’ for [ 3 months and nonspecific bibasilar, expected use of IPF therapy based on disease inspiratory crackles [1, 2]. Pirfenidone is an oral severity in Europe and the United States, and antifibrotic therapy approved for the treatment treatment patterns and prescribing practices of patients with IPF [3–5]. The recommended for antifibrotic therapy in patients with IPF in total daily dose of pirfenidone is 2403 mg/day Europe [13–15]. This real-world study exam- in three equally divided doses, with food [6]. ined practice patterns for treatment with Three multinational, phase III clinical trials antifibrotic therapy (pirfenidone and/or nin- [CAPACITY (Studies 004 and 006; tedanib) in patients with IPF in a geographi- NCT00287716 and NCT00287729) and cally varied sample of pulmonologists in the ASCEND (Study 016; NCT01366209)] investi- United States. In this analysis, we describe gated the efficacy and safety of pirfenidone in strategies for prevention and management of patients with IPF [3, 4]. Pirfenidone slows dis- potential AEs in patients with IPF who are ease progression by reducing the rate of lung receiving pirfenidone. function decline [3, 4]. In a pre-specified pooled analysis of all-cause mortality in ASCEND and Pulm Ther (2018) 4:103–114 105 questions regarding pirfenidone, the survey METHODS reflected clinical experience prior to the com- mercial availability of the 267- or 801-mg pir- Survey Design fenidone tablets, which were launched in the United States in mid-May 2017. Therefore, An online, self-administered, 30-min survey results reflect use of the 267-mg pirfenidone was developed using experts in the fields of capsule only. medicine, epidemiology, health economics, and psychometrics. The survey was individu- Pulmonologist Screening Criteria ally pilot tested by an expert physician in interstitial lung disease (ILD) who advised on the development of the survey so that ques- Healthcare practitioners were eligible to partic- tions were placed in the proper context for ipate in the survey if they were licensed to practice medicine in the United States; were respondents. The survey was additionally pilot tested using a random sample of six ILD board eligible or board certified in pulmonary disease; completed training (residency/fellow- experts and four community-based pulmo- nologists to assess the content, flow, com- ship) [ 1 year prior to participation; spent [ 20% of their time in direct patient care; trea- plexity, and timing for completion of the survey. The identity of the company sponsor- ted patients with IPF with antifibrotic therapy ing the survey, Genentech, Inc., was blinded to (pirfenidone and/or nintedanib); and had C respondents, and respondents’ identities were five patients with IPF on antifibrotic therapy. kept confidential to Genentech, Inc. Addi- tionally, to maintain confidentiality, the sur- Statistical Analyses vey collected information on both approved antifibrotic therapies. Survey responses regarding pirfenidone were The survey was fielded in the United States described using summary statistics, including between April 10, 2017, and May 17, 2017. frequencies and percentages for categorical More than 400 ILD experts—deemed to be data and means (standard deviations) for con- experts in the treatment of pulmonary fibrosis tinuous data. For some questions, participants by way of being part of the Pulmonary Fibrosis were asked to rank the importance of several Foundation’s (PFF) designated PFF Care Center factors using a scale of 1–5, where 1 = ‘‘not Network—were contacted [16]. The compilation important’’ and 5 = ‘‘extremely important’’. of experts was based on the PFF’s experience in Pulmonologists who rated the effectiveness of working with leading medical centers around their specific recommendations for pirfenidone the United States to fund research and improve dosing at mealtimes at mitigating GI-related care [16]. In addition, over 1200 community AEs as a 4 or 5 (‘‘often’’ or ‘‘always’’) were pulmonologists sourced from an external data- compared with those who rated the effective- base of physicians were contacted. For this ness as a1,2, or3(‘‘never’’,‘‘rarely’’, or study, a ‘‘community pulmonologist’’ was ‘‘sometimes’’, respectively). defined as a pulmonologist who did not report When examining advice about sun protec- seeing most of their patients in an ILD center tion according to climate, survey respondents participating in the PFF Care Center Network. were grouped into nine climate regions based As part of the survey, respondents were asked to on the National Centers for Environmental further categorize their main practice setting Information, which categorizes climatically (e.g., academic or community). Respondents consistent regions within the contiguous Uni- answered questions regarding initiation of ted States (Central, East North Central, North- antifibrotic therapy (pirfenidone and/or ninte- east, Northwest, South, Southeast, Southwest, danib), dose titration, and management of West, and West North Central) [17]. Because potential AEs. This analysis specifically focused three regions (Northwest, Southwest, West on real-world strategies for pirfenidone. For North Central) had fewer than ten respondents 106 Pulm Ther (2018) 4:103–114 each, these regions were grouped based on dis- Table 1 Respondent characteristics tance from the equator: Northwest and West Characteristic All respondents North Central were combined with East North (N = 169) Central, and Southwest and South were com- Classification, n (%) bined with West, resulting in five regions: Northeast, Southeast, Central, Northwest/West ILD expert 69 (40.8) North Central/East North Central, and West/ Community pulmonologist 100 (59.2) Southwest/South. Puerto Rico was included in the Southeast region. Years practicing pulmonary medicine, n (%) 1–5 22 (13.0) RESULTS 6–10 35 (20.7) 11–20 60 (35.5) Respondent Characteristics 21–30 47 (27.8) A total of 169 pulmonologists participated in 31–40 5 (3.0) the survey (Table 1). Sixty-nine ILD experts represented referral center practices in 25 states, Professional time spent in direct patient care, n (%) and 100 community pulmonologists repre- 21–40% 3 (1.8) sented practices in 37 states in the United States 41–60% 14 (8.3) (Fig. 1). Approximately one-third of pulmo- nologists [35.5% (n = 60)] had 11–20 years of 61–80% 36 (21.3) experience in pulmonary medicine after com- 81–100% 116 (68.6) pleting their last year of formal training, and approximately one-quarter [27.8% (n = 47)] had Primary practice setting, n (%) 21–30 years of experience. Over two-thirds of Academic 97 (57.4) pulmonologists (68.6%) participating in the survey spent 81–100% of their time in direct Private practice 41 (24.3) patient care. By practice setting, 57.4% of pul- Community 30 (17.8) monologists primarily practiced in an academic Other 1 (0.6) medical center or affiliated teaching hospital, 24.3% in a private practice office, 17.8% in a Patients with IPF in the practice, 66 (109) non-academic community hospital or outpa- mean (SD), n tient clinic, and 0.6% in an ‘‘other’’ practice Patients treated with an approved 55.2 (28.8) setting. The mean [standard deviation (SD)] number of patients with IPF in these practices antifibrotic, mean (SD), % was 66 (109) and ranged from 10 to 1000 ILD interstitial lung disease, IPF idiopathic pulmonary patients. The mean (SD) percentage of patients fibrosis, SD standard deviation with IPF treated with an approved antifibrotic medication (pirfenidone or nintedanib) was and patient comorbidities (Fig. 2). When initi- 55.2% (28.8%). ating treatment with pirfenidone, 119 pulmo- nologists (70.4%) commonly recommended the Initiating Pirfenidone: Dose Titration standard titration scheme (Fig. 3). Non-stan- Schedules dard titration schedules ranging up to 8 weeks were described, with 3- and 4-week schedules GI intolerance was indicated as the most being the most commonly reported non-stan- important factor when deciding to implement dard titration schedules (Fig. 4). an alternative titration schedule for pir- The same initial titration schedule was typi- fenidone, followed by liver enzyme elevations cally recommended by 83.2% of Pulm Ther (2018) 4:103–114 107 Fig. 1 Geographical distribution of survey respondents. Shading represents states with survey participation by pulmonologists Fig. 2 Importance of factors in implementing alternative titration schedules for pirfenidone. 1 not important, 5 extremely important, GI gastrointestinal pulmonologists (n = 139) for all their patients. maintenance dose of pirfenidone using their These pulmonologists reported that an average most commonly recommended titration of 72.9% of their patients reached the full schedule. 108 Pulm Ther (2018) 4:103–114 Fig. 3 Distribution of common initial titration schedules for pirfenidone. Standard, 2-week titration; non-standard, [ 2- week titration; indeterminate, unknown time frame Fig. 4 Commonly reported alternative titration schedules for pirfenidone Initiating Pirfenidone: Dosing recommendations regarding pirfenidone dosing at Mealtimes in relation to the meal, 62.0% (57 of 92) coun- seled their patients to take the dose during the meal (Fig. 5). When initiating pirfenidone treatment, 55.1% When asked how effective their dosing rec- of pulmonologists (92 of 167) advised their ommendations at mealtimes were at mitigating patients to take pirfenidone at mealtimes and pirfenidone-related GI AEs, 47.8% of pulmo- specified when to take it in relation to the meal nologists (44 of 92) rated their advice as being (e.g., before, during, after, or other) (Fig. 5). Of ‘‘often’’ or ‘‘always’’ effective. Of these the pulmonologists who made specific Pulm Ther (2018) 4:103–114 109 a a Fig. 5 Initiation of pirfenidone and recommendations for dosing around mealtimes . 167 pulmonologists reported on the initiation of pirfenidone; of those, 55.1% (n = 92) reported on dosing around mealtimes pulmonologists, 56.8% (25 of 44) were more were common, including sun avoidance likely to recommend taking pirfenidone during (93.4%) and wearing a hat (79.0%). Nearly half a ‘‘substantial’’ meal than those who reported of pulmonologists (46.7%) advised their their dosing recommendations to be less effec- patients to wear ultraviolet protection factor tive at mitigating pirfenidone-related AEs (UPF) clothing (Fig. 7). [43.8% (21 of 48)] (Fig. 6). When examining advice regarding sun pro- tection across the five climate regions, pulmo- nologists in the Northeast and West/Southwest/ Initiating Pirfenidone: Managing South regions were more likely to recommend Photosensitivity the use of sunscreen in patients who spend time outdoors than pulmonologists in the other Most pulmonologists [94.0% (157 of 167)] pro- regions (Table 2). For other strategies for posed the use of sunscreen to their patients who managing photosensitivity, pulmonologists in were initiating pirfenidone and spending time the West/Southwest/South were most likely to outdoors. However, 24 pulmonologists (14.7%) recommend use of UPF clothing; these pulmo- did not proactively recommend the use of sun- nologists and those in the Northwest/West screen to any of their patients or recommended North Central/East North Central region were its use to B 50% of their patients. Of the ten most likely to recommend wearing a hat com- pulmonologists who did not recommend the pared with the other regions (Table 3). use of sunscreen to any of their patients, eight Approximately half of pulmonologists in the recommended sun avoidance and two recom- Southeast recommended UPF clothing. Sun mended ‘‘other strategies’’. Among the 167 avoidance was highly recommended across all pulmonologists who responded, strategies other regions. than the use of sunscreen for managing photo- sensitivity in patients initiating pirfenidone 110 Pulm Ther (2018) 4:103–114 Often or Always Effective (n = 44) Less Effective (n = 48) 4.5% 6.3% 38.6% 50.0% 56.8% 43.8% No, I don't usually specify the size of the meal (n = 17, No, I don't usually specify the size of the meal (n = 24, 38.6%) 50.0%) Yes, usually with a full or substantial meal (breakfast, Yes, usually with a full or substantial meal (breakfast, lunch, dinner) (n = 21, 43.8%) lunch, dinner) (n = 25, 56.8%) Yes, usually with any snack (n = 2, 4.5%) Yes, usually with any snack (n = 3, 6.3%) a a Fig. 6 Perceived effectiveness of dosing recommendations regarding meal size . Of 92 pulmonologists reporting a a Fig. 7 Recommendations other than sunscreen for managing photosensitivity with pirfenidone . Of 167 pulmonologists reporting. UPF ultraviolet protection factor with IPF reduces lung function decline, DISCUSSION improves progression-free survival, and signifi- cantly reduces the risk of all-cause mortality at Randomized, controlled trials have demon- 1year [5]. AE management is critical to helping strated that pirfenidone treatment for patients Pulm Ther (2018) 4:103–114 111 Table 2 Frequency of sunscreen recommendation by An alternative titration schedule was tested in geographic region another study with pirfenidone. In LOTUSS (NCT01933334), a phase II trial that investi- Region Mean percentage of gated pirfenidone in systemic sclerosis ILD (SSc- patients who spend time ILD), a longer titration schedule (4 vs. 2 weeks) outdoors for whom was associated with better tolerability of pir- sunscreen is fenidone [18]. The 4-week titration schedule recommended was tested with pirfenidone in this specific Northeast, n = 56 90.4 population because patients with SSc-ILD may be more susceptible to GI, skin, and liver-related Southeast, n = 30 81.7 AEs due to the nature of their disease [19, 20]. Central, n = 22 80.2 Patients in the 2-week titration group had more dose modifications overall than those in the Northwest/West North 88.3 4-week titration group during the titration per- Central/East North iod [18]. Discontinuation rates due to AEs were Central, n =24 15.6 and 3.2% for the 2- and 4-week titration West/Southwest/South, 91.0 groups, respectively [18]. Patients in the 2- and n =35 4-week groups reported similar AEs, most com- monly nausea, headache, and fatigue, similar to patients with IPF; however, more patients in the some patients maintain long-term treatment. 2-week group experienced a severe AE, suggest- This study provides real-world data from a ing that more gradual titration periods geographically varied sample of pulmonologists of [ 2 weeks may be associated with a better in the United States on strategies for prevention tolerability profile [18]. In this survey, most and management of potential AEs in patients pulmonologists implemented the same initial with IPF who are receiving pirfenidone. titration schedule for all their patients and These real-world survey data suggest that reported that most patients could reach the full alternative titration schedules for initiating maintenance dose of pirfenidone. pirfenidone are common and may aid in The timing and amount of food intake with achieving the full maintenance dose in patients pirfenidone administration appeared to impact with IPF. Non-standard titration schedules pirfenidone-related GI AEs. In this survey, ranging up to 8 weeks were described, and 3- approximately half of the pulmonologists and 4-week titration schedules were the most specifically advised their patients to take pir- commonly reported. These observations are fenidone at mealtimes and provided specific consistent with the clinical trial experience that recommendations on timing. A common and is available for alternative titration schedules. reportedly effective strategy used by these Table 3 Frequency of recommendations for managing photosensitivity by geographic region Region UPF clothing Hats Sun avoidance Other strategies n (%) n (%) n (%) n (%) Northeast 25 (44.6) 44 (78.6) 53 (94.6) 9 (16.1) Southeast 14 (46.7) 22 (73.3) 28 (93.3) 2 (6.7) Central 7 (31.8) 15 (68.2) 19 (86.4) 1 (4.5) Northwest/West North Central/East North 10 (41.7) 21 (87.5) 22 (91.7) 4 (16.7) Central West/Southwest/South 22 (62.9) 30 (85.7) 34 (97.1) 5 (14.3) 112 Pulm Ther (2018) 4:103–114 pulmonologists to ameliorate pirfenidone-re- potentially even lower real-world treatment lated GI AEs was advising taking pirfenidone rates. For example, analyses of the Truven during a substantial meal. This strategy aligns Health MarketScan Commercial and Medicare with what is recommended in the prescribing Supplemental Research Databases from January information as well as what has been advised by 1, 2014, to January 31, 2017, indicated that leading experts in the field [6, 9, 12]. Pre-clinical approximately 2% of enrollees (1192 of 50,296) and pharmacokinetic data have also indicated who had C 1 health care claim associated with a the potential effectiveness of administering diagnosis of IPF (and meeting other criteria) also pirfenidone with a substantial meal to reduce GI had C 1 claim for antifibrotic therapy [22]. AEs. In a phase I study in healthy volunteers Notably, ascertaining rates of antifibrotic use in (NCT02525484) receiving pirfenidone 801 mg a claims database is challenging due to differ- (as three 267-mg capsules) under fasted or fed ences in the case definitions of IPF. Conversely, conditions, GI AEs were decreased in the fed the current study was constructed specifically to state [11]. The pharmacokinetic data indicated examine antifibrotic use in patients with IPF that food reduced the rate and extent of pir- and may not be representative of a more gen- fenidone absorption. In a multivariate statistical eralized IPF population. The disparity in treat- model, a higher maximum plasma concentra- ment patterns between claims data and survey tion (C ) was associated with GI AEs, and data suggests that additional studies are needed max reduction in GI AEs was associated with a lower to better understand key factors in treatment C . Rat gastric emptying models have also decision-making in the real world from both the max investigated the effects of timing pirfenidone physician and patient perspectives and to truly administration and meal intake on GI tolera- capture current practice patterns of pulmo- bility. Results indicated that administering pir- nologists who treat patients with IPF. fenidone with food or dividing the dose over Limitations of these real-world survey data the course of a meal could decrease the C include the potential for response bias, given max and therefore the impact of pirfenidone on that the pulmonologists who were contacted gastric emptying (L Pan et al. Pulm Pharm Ther. and ultimately participated in the survey may Submitted). However, further research is needed be different than those who did not. Thus, it is to better understand the specific mechanism by possible that the data collected may not be fully which pirfenidone impacts gastric emptying. representative of common IPF practices. Addi- Recommendations for managing photosen- tionally, the data collected reflect individual sitivity include use of sunscreen, sun avoidance, physician experiences rather than prospective, and wearing a hat and UPF clothing. These objective measures comparing varying man- strategies also align with recommendations in agement strategies to on-label dosing and the prescribing information as well as those administration. Varying interpretations of the advised by leading experts in the field questions by participants may have also [6, 9, 12, 21]. Data from this survey suggest that impacted responses. For example, one physi- sunscreen use in patients who spend time out- cian’s interpretation of ‘‘extremely important’’ doors may need to be recommended more may be different from another physician’s extensively, particularly in regions such as the interpretation. In collecting data on dose titra- Southeast, where sunshine hours are elevated. tions, there were challenges in accurately However, pulmonologists in all regions were determining and summarizing the alternative highly likely to recommend sun avoidance for titration schemes due to variations in how they managing photosensitivity, which may help were inputted by the respondents. Despite these explain the lower frequency of recommending limitations, the ease and convenience of this UPF clothing in areas such as the Southeast. online pre-programmed survey administered to Pulmonologists in this survey sample repor- a varied sample of pulmonologists allowed the ted that, on average, 55% of patients with IPF capture of real-world IPF practices with a broad were receiving antifibrotic therapy in their range of questions and flexibility in the data practices. Recent analyses of claims data suggest analysis, with minimal opportunities for error Pulm Ther (2018) 4:103–114 113 in administration. The data collected provide article, take responsibility for the integrity of practical and feasible guidance regarding the work as a whole, and have given their strategies for prevention and management of approval for this version to be published. potential AEs in patients with IPF who are Disclosures. Tmirah Haselkorn is a consul- receiving pirfenidone. This guidance expands tant to Genentech, Inc. Susan L. Limb is an on the limited information available in the label employee of Genentech, Inc. John L. Stauffer is and prior expert opinion, reflecting the real- an employee of Genentech, Inc. Karina Rai- world experiences of physicians in a range of mundo is an employee of Genentech, Inc. Eliz- practice settings and broader population of abeth Morgenthien is an employee of patients with IPF receiving antifibrotics. Genentech, Inc. Mark L. Wencel has been a speaker for and received compensation from CONCLUSIONS Genentech, Inc. Peter P. LaCamera has received personal fees for consulting and advisory boards These real-world data from pulmonologists from Genentech, Inc. provide insight into effective practice patterns for managing common pirfenidone-related AEs Compliance with Ethics Guidelines. In- to improve tolerability and treatment persis- formed consent was obtained from all survey tence. These recommended strategies expand participants. This article does not contain any upon what has previously been reported, and interventional or observational studies with alternative dose titration schedules may be an human participants or animals performed by effective method for allowing patients to any of the authors. achieve the full dose of pirfenidone. Data Availability. The datasets generated during and/or analyzed during the current study are not publicly available, as they were ACKNOWLEDGEMENTS generated by a third-party company sponsored by Genentech, Inc., but are available from the The authors would like to thank all of the sur- corresponding author on reasonable request. vey participants as well as Benjamin L. Trza- skoma, MS, for his input on the data and Open Access. This article is distributed statistical analysis. under the terms of the Creative Commons Attribution-NonCommercial 4.0 International Funding. Sponsorship for this study and License (http://creativecommons.org/licenses/ article processing charges were funded by F. by-nc/4.0/), which permits any noncommercial Hoffmann-La Roche Ltd./Genentech, Inc. 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Real-World Practice Patterns for Prevention and Management of Potential Adverse Events with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis

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Medicine & Public Health; Pneumology/Respiratory System; Pharmacotherapy; General Practice / Family Medicine; Internal Medicine; Pharmacoeconomics and Health Outcomes; Quality of Life Research
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10.1007/s41030-018-0056-8
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Abstract

Pulm Ther (2018) 4:103–114 https://doi.org/10.1007/s41030-018-0056-8 ORIGINAL RESEARCH Real-World Practice Patterns for Prevention and Management of Potential Adverse Events with Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis . . . . Mark L. Wencel Tmirah Haselkorn Susan L. Limb John L. Stauffer . . Elizabeth Morgenthien Karina Raimundo Peter P. LaCamera Received: February 28, 2018 / Published online: May 29, 2018 The Author(s) 2018 Results: A total of 169 pulmonologists partici- ABSTRACT pated. Gastrointestinal (GI) intolerance was the most important factor in implementing alter- Introduction: Pirfenidone is an oral antifibrotic native titration schedules for pirfenidone. agent approved for idiopathic pulmonary Approximately three-quarters of pulmonolo- fibrosis (IPF). Real-world data on adverse event gists recommended the standard titration (AE) management for pirfenidone are limited. scheme for starting treatment; however, a range Strategies for managing potential antifibrotic of titration schedules up to 8 weeks were therapy AEs were examined in a sample of US described, with a 4-week schedule being most pulmonologists. common. Pulmonologists reported that most Methods: An online, self-administered survey patients treated with alternative titration was fielded to pulmonologists between April 10 schedules could achieve the full dose of pir- and May 17, 2017. Pulmonologists were inclu- fenidone. Pulmonologists who were most ded if they spent [ 20% of their time in direct effective at mitigating pirfenidone-related GI patient care and had C 5 patients with IPF on AEs by advising dosing at mealtimes more fre- antifibrotic therapy. Participants answered quently recommended taking pirfenidone dur- questions regarding initiation of pirfenidone, ing a substantial meal than pulmonologists who dose titration, and management of potential were less effective. For photosensitivity AEs, AEs. pulmonologists recommended sunscreen use, sun avoidance, wearing a hat, and ultraviolet Enhanced digital features To view enhanced digital protection factor clothing. features for this article go to https://doi.org/10.6084/ m9.figshare.6222455. Conclusions: Pulmonologists reported that alternative titration schedules for initiating M. L. Wencel (&) pirfenidone were common and can aid in Via Christi Health, Wichita, KS, USA maintaining the full dose. Proposed strategies to e-mail: mark.wencel@ascension.org ameliorate pirfenidone-related GI and photo- sensitivity AEs included taking pirfenidone T. Haselkorn EpiMetrix, Inc., Los Altos, CA, USA during a substantial meal and minimizing sun exposure, respectively. S. L. Limb  J. L. Stauffer  E. Morgenthien Funding: F. Hoffmann-La Roche Ltd./Genen- K. Raimundo Genentech, Inc., South San Francisco, CA, USA tech, Inc. Plain Language Summary: Plain language P. P. LaCamera summary available for this article. St. Elizabeth’s Medical Center, Boston, MA, USA 104 Pulm Ther (2018) 4:103–114 Keywords: Adverse event management; CAPACITY, pirfenidone reduced the risk of Antifibrotic therapy; Idiopathic pulmonary death at 1 year by 48% compared with placebo fibrosis; Pirfenidone; Real-world; Titration [3, 7]. For patients receiving pirfenidone, gastrointestinal (GI)- and skin-related adverse events (AEs) are the most common AEs reported PLAIN LANGUAGE SUMMARY [3–5, 8]. These AEs can affect tolerability in some patients, particularly within the first Idiopathic pulmonary fibrosis (IPF) is a deadly 6 months of treatment [9]. In the phase III trials, lung disease. Pirfenidone is a medication that the median time to the first GI AE (in 77.8% of slows down the disease in patients with IPF. patients), rash AE (35.8%), and photosensitivity Stomach- and skin-related side effects are com- AE (9.3%) was 14.0 (range, 5.0–40.0), 82.0 mon with pirfenidone. There is little informa- (range, 49.0–132.0), and 90.0 (range, tion on ways to manage these side effects. In an 48.0–149.0) days, respectively [10]. online survey, US pulmonologists (lung disease A 2-week titration period is recommended specialists) answered questions on how they for pirfenidone, with a starting dose of one start patients on pirfenidone, adjust doses, and 267-mg pill (capsule or tablet) three times daily manage side effects. The use of different dosing (tid) with food for 1 week, followed by two pills schedules when starting pirfenidone was com- tid (534 mg) with food for 1 week and then mon practice among these pulmonologists and three pills (801 mg) tid (maintenance dose) with could help patients stay on pirfenidone if they food [6]. Once maintenance dosing is achieved, had side effects. Taking pirfenidone during a patients may continue to take three 267-mg large meal and staying out of the sun were key pills tid or switch to one 801-mg pill tid, which recommendations for managing common reduces the pill burden in patients receiving stomach and skin side effects. pirfenidone [11]. One empirical method for preventing pir- fenidone-related GI AEs is gradual dose titra- INTRODUCTION tion upon initiation of pirfenidone [9]. Although an expert panel has recommended Idiopathic pulmonary fibrosis (IPF) is a pro- strategies for mitigating pirfenidone AEs and gressive, irreversible, and fatal fibrotic lung dis- management strategies have been proposed on ease [1]. The clinical course of IPF is highly the basis of clinical trial data, real-world data variable and unpredictable in individual on AE management in patients receiving pir- patients; the median survival is 2–5 years from fenidone therapy are limited [9, 12]. Other real- diagnosis [2]. IPF typically presents with unex- world data analyses have focused on efficacy plained dyspnea on exertion or cough and tolerability of pirfenidone, physicians’ for [ 3 months and nonspecific bibasilar, expected use of IPF therapy based on disease inspiratory crackles [1, 2]. Pirfenidone is an oral severity in Europe and the United States, and antifibrotic therapy approved for the treatment treatment patterns and prescribing practices of patients with IPF [3–5]. The recommended for antifibrotic therapy in patients with IPF in total daily dose of pirfenidone is 2403 mg/day Europe [13–15]. This real-world study exam- in three equally divided doses, with food [6]. ined practice patterns for treatment with Three multinational, phase III clinical trials antifibrotic therapy (pirfenidone and/or nin- [CAPACITY (Studies 004 and 006; tedanib) in patients with IPF in a geographi- NCT00287716 and NCT00287729) and cally varied sample of pulmonologists in the ASCEND (Study 016; NCT01366209)] investi- United States. In this analysis, we describe gated the efficacy and safety of pirfenidone in strategies for prevention and management of patients with IPF [3, 4]. Pirfenidone slows dis- potential AEs in patients with IPF who are ease progression by reducing the rate of lung receiving pirfenidone. function decline [3, 4]. In a pre-specified pooled analysis of all-cause mortality in ASCEND and Pulm Ther (2018) 4:103–114 105 questions regarding pirfenidone, the survey METHODS reflected clinical experience prior to the com- mercial availability of the 267- or 801-mg pir- Survey Design fenidone tablets, which were launched in the United States in mid-May 2017. Therefore, An online, self-administered, 30-min survey results reflect use of the 267-mg pirfenidone was developed using experts in the fields of capsule only. medicine, epidemiology, health economics, and psychometrics. The survey was individu- Pulmonologist Screening Criteria ally pilot tested by an expert physician in interstitial lung disease (ILD) who advised on the development of the survey so that ques- Healthcare practitioners were eligible to partic- tions were placed in the proper context for ipate in the survey if they were licensed to practice medicine in the United States; were respondents. The survey was additionally pilot tested using a random sample of six ILD board eligible or board certified in pulmonary disease; completed training (residency/fellow- experts and four community-based pulmo- nologists to assess the content, flow, com- ship) [ 1 year prior to participation; spent [ 20% of their time in direct patient care; trea- plexity, and timing for completion of the survey. The identity of the company sponsor- ted patients with IPF with antifibrotic therapy ing the survey, Genentech, Inc., was blinded to (pirfenidone and/or nintedanib); and had C respondents, and respondents’ identities were five patients with IPF on antifibrotic therapy. kept confidential to Genentech, Inc. Addi- tionally, to maintain confidentiality, the sur- Statistical Analyses vey collected information on both approved antifibrotic therapies. Survey responses regarding pirfenidone were The survey was fielded in the United States described using summary statistics, including between April 10, 2017, and May 17, 2017. frequencies and percentages for categorical More than 400 ILD experts—deemed to be data and means (standard deviations) for con- experts in the treatment of pulmonary fibrosis tinuous data. For some questions, participants by way of being part of the Pulmonary Fibrosis were asked to rank the importance of several Foundation’s (PFF) designated PFF Care Center factors using a scale of 1–5, where 1 = ‘‘not Network—were contacted [16]. The compilation important’’ and 5 = ‘‘extremely important’’. of experts was based on the PFF’s experience in Pulmonologists who rated the effectiveness of working with leading medical centers around their specific recommendations for pirfenidone the United States to fund research and improve dosing at mealtimes at mitigating GI-related care [16]. In addition, over 1200 community AEs as a 4 or 5 (‘‘often’’ or ‘‘always’’) were pulmonologists sourced from an external data- compared with those who rated the effective- base of physicians were contacted. For this ness as a1,2, or3(‘‘never’’,‘‘rarely’’, or study, a ‘‘community pulmonologist’’ was ‘‘sometimes’’, respectively). defined as a pulmonologist who did not report When examining advice about sun protec- seeing most of their patients in an ILD center tion according to climate, survey respondents participating in the PFF Care Center Network. were grouped into nine climate regions based As part of the survey, respondents were asked to on the National Centers for Environmental further categorize their main practice setting Information, which categorizes climatically (e.g., academic or community). Respondents consistent regions within the contiguous Uni- answered questions regarding initiation of ted States (Central, East North Central, North- antifibrotic therapy (pirfenidone and/or ninte- east, Northwest, South, Southeast, Southwest, danib), dose titration, and management of West, and West North Central) [17]. Because potential AEs. This analysis specifically focused three regions (Northwest, Southwest, West on real-world strategies for pirfenidone. For North Central) had fewer than ten respondents 106 Pulm Ther (2018) 4:103–114 each, these regions were grouped based on dis- Table 1 Respondent characteristics tance from the equator: Northwest and West Characteristic All respondents North Central were combined with East North (N = 169) Central, and Southwest and South were com- Classification, n (%) bined with West, resulting in five regions: Northeast, Southeast, Central, Northwest/West ILD expert 69 (40.8) North Central/East North Central, and West/ Community pulmonologist 100 (59.2) Southwest/South. Puerto Rico was included in the Southeast region. Years practicing pulmonary medicine, n (%) 1–5 22 (13.0) RESULTS 6–10 35 (20.7) 11–20 60 (35.5) Respondent Characteristics 21–30 47 (27.8) A total of 169 pulmonologists participated in 31–40 5 (3.0) the survey (Table 1). Sixty-nine ILD experts represented referral center practices in 25 states, Professional time spent in direct patient care, n (%) and 100 community pulmonologists repre- 21–40% 3 (1.8) sented practices in 37 states in the United States 41–60% 14 (8.3) (Fig. 1). Approximately one-third of pulmo- nologists [35.5% (n = 60)] had 11–20 years of 61–80% 36 (21.3) experience in pulmonary medicine after com- 81–100% 116 (68.6) pleting their last year of formal training, and approximately one-quarter [27.8% (n = 47)] had Primary practice setting, n (%) 21–30 years of experience. Over two-thirds of Academic 97 (57.4) pulmonologists (68.6%) participating in the survey spent 81–100% of their time in direct Private practice 41 (24.3) patient care. By practice setting, 57.4% of pul- Community 30 (17.8) monologists primarily practiced in an academic Other 1 (0.6) medical center or affiliated teaching hospital, 24.3% in a private practice office, 17.8% in a Patients with IPF in the practice, 66 (109) non-academic community hospital or outpa- mean (SD), n tient clinic, and 0.6% in an ‘‘other’’ practice Patients treated with an approved 55.2 (28.8) setting. The mean [standard deviation (SD)] number of patients with IPF in these practices antifibrotic, mean (SD), % was 66 (109) and ranged from 10 to 1000 ILD interstitial lung disease, IPF idiopathic pulmonary patients. The mean (SD) percentage of patients fibrosis, SD standard deviation with IPF treated with an approved antifibrotic medication (pirfenidone or nintedanib) was and patient comorbidities (Fig. 2). When initi- 55.2% (28.8%). ating treatment with pirfenidone, 119 pulmo- nologists (70.4%) commonly recommended the Initiating Pirfenidone: Dose Titration standard titration scheme (Fig. 3). Non-stan- Schedules dard titration schedules ranging up to 8 weeks were described, with 3- and 4-week schedules GI intolerance was indicated as the most being the most commonly reported non-stan- important factor when deciding to implement dard titration schedules (Fig. 4). an alternative titration schedule for pir- The same initial titration schedule was typi- fenidone, followed by liver enzyme elevations cally recommended by 83.2% of Pulm Ther (2018) 4:103–114 107 Fig. 1 Geographical distribution of survey respondents. Shading represents states with survey participation by pulmonologists Fig. 2 Importance of factors in implementing alternative titration schedules for pirfenidone. 1 not important, 5 extremely important, GI gastrointestinal pulmonologists (n = 139) for all their patients. maintenance dose of pirfenidone using their These pulmonologists reported that an average most commonly recommended titration of 72.9% of their patients reached the full schedule. 108 Pulm Ther (2018) 4:103–114 Fig. 3 Distribution of common initial titration schedules for pirfenidone. Standard, 2-week titration; non-standard, [ 2- week titration; indeterminate, unknown time frame Fig. 4 Commonly reported alternative titration schedules for pirfenidone Initiating Pirfenidone: Dosing recommendations regarding pirfenidone dosing at Mealtimes in relation to the meal, 62.0% (57 of 92) coun- seled their patients to take the dose during the meal (Fig. 5). When initiating pirfenidone treatment, 55.1% When asked how effective their dosing rec- of pulmonologists (92 of 167) advised their ommendations at mealtimes were at mitigating patients to take pirfenidone at mealtimes and pirfenidone-related GI AEs, 47.8% of pulmo- specified when to take it in relation to the meal nologists (44 of 92) rated their advice as being (e.g., before, during, after, or other) (Fig. 5). Of ‘‘often’’ or ‘‘always’’ effective. Of these the pulmonologists who made specific Pulm Ther (2018) 4:103–114 109 a a Fig. 5 Initiation of pirfenidone and recommendations for dosing around mealtimes . 167 pulmonologists reported on the initiation of pirfenidone; of those, 55.1% (n = 92) reported on dosing around mealtimes pulmonologists, 56.8% (25 of 44) were more were common, including sun avoidance likely to recommend taking pirfenidone during (93.4%) and wearing a hat (79.0%). Nearly half a ‘‘substantial’’ meal than those who reported of pulmonologists (46.7%) advised their their dosing recommendations to be less effec- patients to wear ultraviolet protection factor tive at mitigating pirfenidone-related AEs (UPF) clothing (Fig. 7). [43.8% (21 of 48)] (Fig. 6). When examining advice regarding sun pro- tection across the five climate regions, pulmo- nologists in the Northeast and West/Southwest/ Initiating Pirfenidone: Managing South regions were more likely to recommend Photosensitivity the use of sunscreen in patients who spend time outdoors than pulmonologists in the other Most pulmonologists [94.0% (157 of 167)] pro- regions (Table 2). For other strategies for posed the use of sunscreen to their patients who managing photosensitivity, pulmonologists in were initiating pirfenidone and spending time the West/Southwest/South were most likely to outdoors. However, 24 pulmonologists (14.7%) recommend use of UPF clothing; these pulmo- did not proactively recommend the use of sun- nologists and those in the Northwest/West screen to any of their patients or recommended North Central/East North Central region were its use to B 50% of their patients. Of the ten most likely to recommend wearing a hat com- pulmonologists who did not recommend the pared with the other regions (Table 3). use of sunscreen to any of their patients, eight Approximately half of pulmonologists in the recommended sun avoidance and two recom- Southeast recommended UPF clothing. Sun mended ‘‘other strategies’’. Among the 167 avoidance was highly recommended across all pulmonologists who responded, strategies other regions. than the use of sunscreen for managing photo- sensitivity in patients initiating pirfenidone 110 Pulm Ther (2018) 4:103–114 Often or Always Effective (n = 44) Less Effective (n = 48) 4.5% 6.3% 38.6% 50.0% 56.8% 43.8% No, I don't usually specify the size of the meal (n = 17, No, I don't usually specify the size of the meal (n = 24, 38.6%) 50.0%) Yes, usually with a full or substantial meal (breakfast, Yes, usually with a full or substantial meal (breakfast, lunch, dinner) (n = 21, 43.8%) lunch, dinner) (n = 25, 56.8%) Yes, usually with any snack (n = 2, 4.5%) Yes, usually with any snack (n = 3, 6.3%) a a Fig. 6 Perceived effectiveness of dosing recommendations regarding meal size . Of 92 pulmonologists reporting a a Fig. 7 Recommendations other than sunscreen for managing photosensitivity with pirfenidone . Of 167 pulmonologists reporting. UPF ultraviolet protection factor with IPF reduces lung function decline, DISCUSSION improves progression-free survival, and signifi- cantly reduces the risk of all-cause mortality at Randomized, controlled trials have demon- 1year [5]. AE management is critical to helping strated that pirfenidone treatment for patients Pulm Ther (2018) 4:103–114 111 Table 2 Frequency of sunscreen recommendation by An alternative titration schedule was tested in geographic region another study with pirfenidone. In LOTUSS (NCT01933334), a phase II trial that investi- Region Mean percentage of gated pirfenidone in systemic sclerosis ILD (SSc- patients who spend time ILD), a longer titration schedule (4 vs. 2 weeks) outdoors for whom was associated with better tolerability of pir- sunscreen is fenidone [18]. The 4-week titration schedule recommended was tested with pirfenidone in this specific Northeast, n = 56 90.4 population because patients with SSc-ILD may be more susceptible to GI, skin, and liver-related Southeast, n = 30 81.7 AEs due to the nature of their disease [19, 20]. Central, n = 22 80.2 Patients in the 2-week titration group had more dose modifications overall than those in the Northwest/West North 88.3 4-week titration group during the titration per- Central/East North iod [18]. Discontinuation rates due to AEs were Central, n =24 15.6 and 3.2% for the 2- and 4-week titration West/Southwest/South, 91.0 groups, respectively [18]. Patients in the 2- and n =35 4-week groups reported similar AEs, most com- monly nausea, headache, and fatigue, similar to patients with IPF; however, more patients in the some patients maintain long-term treatment. 2-week group experienced a severe AE, suggest- This study provides real-world data from a ing that more gradual titration periods geographically varied sample of pulmonologists of [ 2 weeks may be associated with a better in the United States on strategies for prevention tolerability profile [18]. In this survey, most and management of potential AEs in patients pulmonologists implemented the same initial with IPF who are receiving pirfenidone. titration schedule for all their patients and These real-world survey data suggest that reported that most patients could reach the full alternative titration schedules for initiating maintenance dose of pirfenidone. pirfenidone are common and may aid in The timing and amount of food intake with achieving the full maintenance dose in patients pirfenidone administration appeared to impact with IPF. Non-standard titration schedules pirfenidone-related GI AEs. In this survey, ranging up to 8 weeks were described, and 3- approximately half of the pulmonologists and 4-week titration schedules were the most specifically advised their patients to take pir- commonly reported. These observations are fenidone at mealtimes and provided specific consistent with the clinical trial experience that recommendations on timing. A common and is available for alternative titration schedules. reportedly effective strategy used by these Table 3 Frequency of recommendations for managing photosensitivity by geographic region Region UPF clothing Hats Sun avoidance Other strategies n (%) n (%) n (%) n (%) Northeast 25 (44.6) 44 (78.6) 53 (94.6) 9 (16.1) Southeast 14 (46.7) 22 (73.3) 28 (93.3) 2 (6.7) Central 7 (31.8) 15 (68.2) 19 (86.4) 1 (4.5) Northwest/West North Central/East North 10 (41.7) 21 (87.5) 22 (91.7) 4 (16.7) Central West/Southwest/South 22 (62.9) 30 (85.7) 34 (97.1) 5 (14.3) 112 Pulm Ther (2018) 4:103–114 pulmonologists to ameliorate pirfenidone-re- potentially even lower real-world treatment lated GI AEs was advising taking pirfenidone rates. For example, analyses of the Truven during a substantial meal. This strategy aligns Health MarketScan Commercial and Medicare with what is recommended in the prescribing Supplemental Research Databases from January information as well as what has been advised by 1, 2014, to January 31, 2017, indicated that leading experts in the field [6, 9, 12]. Pre-clinical approximately 2% of enrollees (1192 of 50,296) and pharmacokinetic data have also indicated who had C 1 health care claim associated with a the potential effectiveness of administering diagnosis of IPF (and meeting other criteria) also pirfenidone with a substantial meal to reduce GI had C 1 claim for antifibrotic therapy [22]. AEs. In a phase I study in healthy volunteers Notably, ascertaining rates of antifibrotic use in (NCT02525484) receiving pirfenidone 801 mg a claims database is challenging due to differ- (as three 267-mg capsules) under fasted or fed ences in the case definitions of IPF. Conversely, conditions, GI AEs were decreased in the fed the current study was constructed specifically to state [11]. The pharmacokinetic data indicated examine antifibrotic use in patients with IPF that food reduced the rate and extent of pir- and may not be representative of a more gen- fenidone absorption. In a multivariate statistical eralized IPF population. The disparity in treat- model, a higher maximum plasma concentra- ment patterns between claims data and survey tion (C ) was associated with GI AEs, and data suggests that additional studies are needed max reduction in GI AEs was associated with a lower to better understand key factors in treatment C . Rat gastric emptying models have also decision-making in the real world from both the max investigated the effects of timing pirfenidone physician and patient perspectives and to truly administration and meal intake on GI tolera- capture current practice patterns of pulmo- bility. Results indicated that administering pir- nologists who treat patients with IPF. fenidone with food or dividing the dose over Limitations of these real-world survey data the course of a meal could decrease the C include the potential for response bias, given max and therefore the impact of pirfenidone on that the pulmonologists who were contacted gastric emptying (L Pan et al. Pulm Pharm Ther. and ultimately participated in the survey may Submitted). However, further research is needed be different than those who did not. Thus, it is to better understand the specific mechanism by possible that the data collected may not be fully which pirfenidone impacts gastric emptying. representative of common IPF practices. Addi- Recommendations for managing photosen- tionally, the data collected reflect individual sitivity include use of sunscreen, sun avoidance, physician experiences rather than prospective, and wearing a hat and UPF clothing. These objective measures comparing varying man- strategies also align with recommendations in agement strategies to on-label dosing and the prescribing information as well as those administration. Varying interpretations of the advised by leading experts in the field questions by participants may have also [6, 9, 12, 21]. Data from this survey suggest that impacted responses. For example, one physi- sunscreen use in patients who spend time out- cian’s interpretation of ‘‘extremely important’’ doors may need to be recommended more may be different from another physician’s extensively, particularly in regions such as the interpretation. In collecting data on dose titra- Southeast, where sunshine hours are elevated. tions, there were challenges in accurately However, pulmonologists in all regions were determining and summarizing the alternative highly likely to recommend sun avoidance for titration schemes due to variations in how they managing photosensitivity, which may help were inputted by the respondents. Despite these explain the lower frequency of recommending limitations, the ease and convenience of this UPF clothing in areas such as the Southeast. online pre-programmed survey administered to Pulmonologists in this survey sample repor- a varied sample of pulmonologists allowed the ted that, on average, 55% of patients with IPF capture of real-world IPF practices with a broad were receiving antifibrotic therapy in their range of questions and flexibility in the data practices. Recent analyses of claims data suggest analysis, with minimal opportunities for error Pulm Ther (2018) 4:103–114 113 in administration. The data collected provide article, take responsibility for the integrity of practical and feasible guidance regarding the work as a whole, and have given their strategies for prevention and management of approval for this version to be published. potential AEs in patients with IPF who are Disclosures. Tmirah Haselkorn is a consul- receiving pirfenidone. This guidance expands tant to Genentech, Inc. Susan L. Limb is an on the limited information available in the label employee of Genentech, Inc. John L. Stauffer is and prior expert opinion, reflecting the real- an employee of Genentech, Inc. Karina Rai- world experiences of physicians in a range of mundo is an employee of Genentech, Inc. Eliz- practice settings and broader population of abeth Morgenthien is an employee of patients with IPF receiving antifibrotics. Genentech, Inc. Mark L. Wencel has been a speaker for and received compensation from CONCLUSIONS Genentech, Inc. Peter P. LaCamera has received personal fees for consulting and advisory boards These real-world data from pulmonologists from Genentech, Inc. provide insight into effective practice patterns for managing common pirfenidone-related AEs Compliance with Ethics Guidelines. In- to improve tolerability and treatment persis- formed consent was obtained from all survey tence. These recommended strategies expand participants. This article does not contain any upon what has previously been reported, and interventional or observational studies with alternative dose titration schedules may be an human participants or animals performed by effective method for allowing patients to any of the authors. achieve the full dose of pirfenidone. Data Availability. The datasets generated during and/or analyzed during the current study are not publicly available, as they were ACKNOWLEDGEMENTS generated by a third-party company sponsored by Genentech, Inc., but are available from the The authors would like to thank all of the sur- corresponding author on reasonable request. vey participants as well as Benjamin L. Trza- skoma, MS, for his input on the data and Open Access. This article is distributed statistical analysis. under the terms of the Creative Commons Attribution-NonCommercial 4.0 International Funding. Sponsorship for this study and License (http://creativecommons.org/licenses/ article processing charges were funded by F. by-nc/4.0/), which permits any noncommercial Hoffmann-La Roche Ltd./Genentech, Inc. 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Journal

Pulmonary TherapySpringer Journals

Published: May 29, 2018

References

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