CLINICAL MONOGRAPH Clinical Mono… · Raghu G, et al. Idiopathic interstitial pneumonia: what is...

Please see Important Safety Information on pages 14-16 and click here for full Prescribing Information, including Patient Information.

CLINICAL MONOGRAPHINDICATIONS OFEV® (nintedanib) capsules is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

OFEV is indicated to slow the rate of decline in pulmonary function in patients with systemic sclerosis–associated interstitial lung disease (SSc-ILD).

http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Ofev/ofev.pdf

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EXECUTIVE SUMMARY ............................................................................................................3-4References 4IPF OVERVIEW ..................................................................................................................................5-10Incidence and prevalence 5Pathophysiology 6Approved treatment options 7-8Conclusions 8Other treatment considerations 9References 10SSc-ILD OVERVIEW .....................................................................................................................11-13SSc disease overview 11Lung involvement in SSc 11Risk factors for SSc-ILD 12Mortality in SSc-ILD 12References 13IMPORTANT SAFETY INFORMATION .........................................................................14-16PRODUCT DESCRIPTION .......................................................................................................17-20Indications and usage 17Description 17Dosage and administration 18-19How supplied/storage and handling 19Reference 20CLINICAL PHARMACOLOGY ...............................................................................................21-25Mechanism of action 21Pharmacodynamics 21Pharmacokinetics 21-24Reference 25CLINICAL EFFICACY ....................................................................................................................26-35IPF .................................................................................................................................................................26-30Clinical studies description 26-27Annual rate of decline in FVC 27-28Change from baseline in percent predicted FVC 29Time to first acute IPF exacerbation 30Survival analysis 30SSc-ILD .....................................................................................................................................................31-35Clinical study description 31Annual rate of decline in FVC 32-33Change from baseline in percent predicted FVC 34Modified Rodnan Skin Score 34Survival 34References 35SAFETY PROFILE ............................................................................................................................36-45IPF .................................................................................................................................................................36-41Clinical studies experience 36-37Additional safety data 38-40 Overdosage 41SSc-ILD .....................................................................................................................................................41-45Clinical study experience 41-42Additional safety data 43-44References 45USE IN SPECIFIC POPULATIONS .....................................................................................46-49Reference 49

CONTENTS


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EXECUTIVE SUMMARYIDIOPATHIC PULMONARY FIBROSIS (IPF) IPF is a rare and serious lung disease with an unknown etiology.1-5,a According to the American Thoracic Society (ATS), the European Respiratory Society (ERS), the Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT), IPF is defined as a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs.5

For healthcare professionals, diagnosing IPF can be a challenge.5-8 Patients are often misdiagnosed with other conditions, such as bronchitis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, or heart disease.8 The accuracy of an IPF diagnosis increases with multidisciplinary discussion between IPF experts, including pulmonologists, radiologists, and pathologists.5,9

SYSTEMIC SCLEROSIS–ASSOCIATED INTERSTITIAL LUNG DISEASE (SSc-ILD) Systemic sclerosis (SSc) is a rare and serious chronic autoimmune disease that is incompletely understood.10-13 Patients with SSc can experience a range of mild to life-threatening manifestations, particularly involving the lungs.13,14

Interstitial lung disease (ILD) is a common, life-limiting manifestation of SSc.14,15 Up to 90% of patients will have ILD seen on high-resolution computed tomography (HRCT), while 40% to 75% will show evidence based on pulmonary function tests. Approximately 25% of patients with SSc will have clinically relevant ILD.13 The impact of SSc-ILD ranges from subclinical lung involvement to major pulmonary disease progressing to respiratory failure and death.14,16 SSc-ILD occurs in both diffuse cutaneous SSc (dcSSc) (53%) and limited cutaneous SSc (lcSSc) (35%).17

SSc-ILD can lead to considerable morbidity in patients, and it is the leading cause of mortality in SSc.18

a The Rare Diseases Act of 2002 defines orphan diseases as rare diseases and disorders that affect small populations (typically, populations smaller than 200,000 individuals in the United States).1


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REFERENCES1. Rare Diseases Act. Pub L No. 107-280, 116 Stat 1988. 2. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(7):810-816. 3. Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis. 2008;3:8. 4. Adamali HI, Anwar MS, Russell AM, Egan JJ. Non-pharmacological treatment of idiopathic pulmonary fibrosis. Curr Respir Care Rep. 2012;1(4):208-215. 5. Raghu G, Remy-Jardin M, Myers JL; on behalf of American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. Diagnosis of idiopathic pulmonary fibrosis: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68. 6. Douglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med. 2000;161(4 pt 1):1172-1178. 7. King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med. 2001;164(7):1171-1181. 8. Collard HR, Tino G, Noble PW, et al. Patient experiences with pulmonary fibrosis. Respir Med. 2007;101(6):1350-1354. 9. Flaherty KR, King TE Jr, Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med. 2004;170(8):904-910. 10. Al-Dhaher FF, Pope JE, Ouimet JM. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin Arthritis Rheum. 2010;39(4):269-277. 11. Fan Y, Bender S, Shi W, Shao N, Zoz D. Prevalence and incidence of systemic sclerosis and systemic sclerosis with interstitial lung disease in the US. Poster presented at: AMCP Nexus 2018 Conference; October 24, 2018; Orlando, FL. 12. Ranque B, Mouthon L. Geoepidemiology of systemic sclerosis. Autoimmun Rev. 2010;9(5):A311-A318. 13. Solomon JJ, Olson AL, Fischer A, Bull T, Brown KK, Raghu G. Scleroderma lung disease. Eur Respir Rev. 2013;22(127):6-19. 14. Wells AU. Interstitial lung disease in systemic sclerosis. Presse Med. 2014;43(10 pt 2):e329-e343. 15. Varga J. Systemic sclerosis: an update. Bull NYU Hosp Jt Dis. 2008;66(3):198-202. 16. Tan A, Denton CP, Mikhailidis DP, Seifalian AM. Recent advances in the diagnosis and treatment of interstitial lung disease in systemic sclerosis (scleroderma): a review. Clin Exp Rheumatol. 2011;29(2 Suppl 65):S66-S74. 17. Walker UA, Tyndall A, Czirjåk L, et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group database. Ann Rheum Dis. 2007;66(6):754-763. 18. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007;66(7):940-944.


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INCIDENCE AND PREVALENCE IPF is considered a rare disease,a defined as a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause.1,2 Although rare, the prevalence of IPF is steadily increasing, especially in the elderly population, with a median age at diagnosis of 66 years.3-6 The 2010 prevalence of IPF was estimated at 6.7b and 131.1c per 100,000 person-years in commercially insured and Medicare populations, respectively.3,4 For the same year, incidence of IPF in commercially insured and Medicare populations was 2.4b and 28.0c per 100,000 person-years, respectively.3,4

IPF OVERVIEW

a The Rare Diseases Act of 2002 defines orphan diseases as rare diseases and disorders that affect small populations (typically, populations smaller than 200,000 individuals in the United States).1

b Narrow case subgroup (n=1685): A subgroup of the primary cohort that included patients with IPF meeting the broad case definition (no International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] diagnosis code 515 on or after the last diagnosis code 516.3) who also had evidence of a prior diagnostic test, including surgical lung biopsy, transbronchial lung biopsy, or computed tomography (CT) scan of the thorax in the broad case subgroup prior to the last diagnosis code 516.3.3

c Narrow case subgroup (n=3195): A subgroup of the primary cohort that included Medicare beneficiaries with IPF meeting the broad case definition (no ICD-10-CM diagnosis code 515 on or after the quarter of the last claim with diagnosis code 516.3) who also had a claim for a surgical lung biopsy, transbronchial lung biopsy, or CT scan of the thorax before the last claim with the ICD-10-CM diagnosis code 516.3 recorded in the database.4

Incidence and prevalence of IPF in the commercially insured population aged 18 to 64 years (2005–2010)3,b

Adapted from Raghu G et al 2016.3 Adapted from Raghu G et al 2014.4

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IPF OVERVIEW (cont’d)PATHOPHYSIOLOGYResearchers are looking to clarify the underlying pathophysiology of IPF to help them better inform IPF diagnosis and treatment decisions.7,8 There is a theory that IPF is initially formed by repetitive injuries to the alveolar epithelium.7 These injuries initiate fibroblast migration and proliferation.7,8 The continuous disruption of the alveolar epithelial cell layer or basement membrane causes an imbalance in proteases and antiproteases, resulting in increased angiogenesis and myofibroblast foci formation leading to fibrosis.7


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APPROVED TREATMENT OPTIONSThere are US Food and Drug Administration (FDA)–approved pharmacologic treatments recommendeda for use in the 2015 ATS/ERS/JRS/ALAT guideline.9,a

Recommendation for the use of OFEV® (nintedanib) capsulesThe recommendation for the use of OFEV in IPF patients is conditional, with moderate confidence in effect estimates.

Interpretation of this conditional recommendation for patients and clinicians9

• The majority of patients would want OFEV treatment, but many would not

• Clinicians should recognize that different choices will be appropriate for individual patients and each patient must be helped to arrive at a management decision consistent with his or her values and preferences

Justifications and considerationsIn making this recommendation, the 2015 guideline places a high value on the potential benefit of OFEV on outcomes important to patients, such as disease progression, as measured by9:

• The rate of forced vital capacity (FVC) decline

• Mortality

A lower value is placed on9:

• Potentially significant adverse effects

• Expected treatment cost

IPF OVERVIEW (cont’d)

a The pharmacologic treatments recommended in the 2015 guideline are conditional. There are no pharmacologic treatments that received strong recommendations for use in the 2015 guideline.9


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APPROVED TREATMENT OPTIONS (cont’d)Considerations include9:

• No significant effect on overall mortality was seen with OFEV® (nintedanib) capsules

• The concerns based on current costs may limit feasibility and use

• Adverse effects were commonly reported with OFEV, specifically diarrhea, and patients must be informed of these risks when making treatment decisions

• Available evidence focuses only on patients with IPF with mild to moderate lung function impairment (FVC ≥50%) in pulmonary function tests and it is unknown whether benefits would differ in more severe patients

CONCLUSIONS When treating patients with IPF, clinicians are advised to9:

• Individualize therapy decisions with their patients, as suggested by this conditional recommendation

• Exercise caution in comparing the relative net benefits of interventions because of factors including variations in patient inclusion criteria in clinical trialsa

• Avoid inferring that guideline recommendations of similar strength (ie, grade) will achieve the same net benefit or harm

• Consider significant variations in inclusion criteria, the confidence in effect estimates, and cost to be important factors


aEach recommendation’s strength is the net result of multiple factors that may be different in type and intensity.


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OTHER TREATMENT CONSIDERATIONSFor patients with IPF who meet eligibility requirements, lung transplantation is a possible treatment option.10,11 In fact, the percentage of patients with IPF undergoing lung transplant has steadily increased from 21% in 2002 to 38% in 2011.12 Lung transplants have been shown to improve both life expectancy and quality of life in people with IPF.13

The 5-year survival rate after lung transplantation in patients with IPF is estimated to be 50% to 56%.14 Although lung transplant is a viable option for some patients, it can pose considerable clinical and cost burden. The average length of stay in the hospital for single and double lung transplants is 21.2 and 29.5 days, respectively.15 Furthermore, according to one cost analysis, the estimated average charges per transplant in the United States are approximately $785,000 for a single lung transplant and can reach more than $1 million for a double lung transplant.15

In addition to lung transplant as a possible option, other management options for IPF may include supplemental oxygen, pulmonary rehabilitation, antifibrotic therapy, and management of comorbidities.9,14,16,17



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REFERENCES1. Rare Diseases Act. Pub L No. 107-280, 116 Stat 1988. 2. Raghu G, Remy-Jardin M, Myers JL; on behalf of American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68. 3. Raghu G, Chen SY, Hou Q, Yeh WS, Collard HR. Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old. Eur Respir J. 2016;48(1):179-186. 4. Raghu G, Chen SY, Yeh WS, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med. 2014;2(7):566-572. 5. Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-440. 6. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161(2 pt 1):646-664. 7. Fernandez IE, Eickelberg O. New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet. 2012;380(9842):680-688. 8. Maher TM. Idiopathic pulmonary fibrosis: pathobiology of novel approaches to treatment. Clin Chest Med. 2012;33(1):69-83. 9. Raghu G, Rochwerg B, Zhang Y, et al; on behalf of the ATS, ERS, JRS, and ALAT. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015;192(2):e3-e19. 10. Nathan SD, Shlobin OA, Weir N, et al. Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest. 2011;140(1):221-229. 11. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25(7):745-755. 12. Transplant recipient characteristics, 2002 to 2011 recipients of deceased donor lungs by primary diagnosis. Scientific Registry of Transplant Recipients website. https://srtr.transplant.hrsa.gov/annual_reports/2011/pdf/2011_SRTR_ADR.pdf. Accessed July 1, 2019. 13. Chest Foundation. Pulmonary fibrosis. https://foundation.chestnet.org/pf/. Accessed October 3, 2019. 14. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. 15. Bentley TS. 2014 U.S. organ and tissue transplant cost estimates and discussion. Milliman website. http://www.milliman.com/uploadedFiles/insight/Research/health-rr/1938HDP_20141230.pdf. Published December 30, 2014. Accessed July 1, 2019. 16. Raghu G, Richeldi L. Current approaches to the management of idiopathic pulmonary fibrosis. Respir Med. 2017;129:24-30. 17. Van Manen MJ, Geelhoed JJ, Tak NC, Wijsenbeek MS. Optimizing quality of life in patients with idiopathic pulmonary fibrosis. Ther Adv Respir Dis. 2017;11(3):157-169.


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SSc DISEASE OVERVIEWSystemic sclerosis (SSc) is a rare and serious chronic autoimmune disease that is incompletely understood.1 The disease is complex, variable, and unpredictable.2-4 Patients with SSc can experience a range of mild to life-threatening systemic manifestations, and the lungs are an important site of SSc.5,6 Pathologic organ involvement in SSc tends to occur in the early stages of the disease.7

The disease is rare with an estimated US prevalence of ~26 patients per 100,000. Of those

affected, nearly 60% are under the age of 65%, and an estimated 85% are female.8

Prevalence per 100,000 US state Period

26.47 All states8 2011-2016

30.0 All states9 2001-2002

18.4 All states10 2003-2008

27.6 Michigan9,a 1989-1991

29.0-113 South Carolina9,a 1989

Incidence per 100,000 person-years US state Period

7.40 All states8 2011-2016

5.61 All states10 2003-2008

2.10 Michigan9,a 1989-1991

1.41 Michigan9,a 1985-1991

Nearly 60% of the patient population is younger than 65 years of age8

85% Female

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65+

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An estimated 85% of patients with SSc are female8

Age of patients with SSc

Gender of patients with SSc

SSc-ILD OVERVIEW

aStudy population was limited to this state.

LUNG INVOLVEMENT IN SScThere are different subtypes of SSc, including diffuse cutaneous, limited cutaneous, and the rarest form, sine scleroderma, and lung involvement can be a manifestation of all of them.7 ILD is one of the more common life-limiting manifestations in SSc.6,11

Up to 90% of patients will have ILD seen on HRCT, while 40% to 75% will show evidence based on pulmonary function tests. Of those patients, approximately 25% will have clinically relevant ILD.5 The impact of SSc-ILD ranges from subclinical lung involvement to major pulmonary disease progressing to respiratory failure and death.6,12 In addition, progressive scarring of the lung tissue around alveoli in ILD results in reduced oxygen in the bloodstream.13,14


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SSc-ILD OVERVIEW (cont’d)RISK FACTORS FOR SSc-ILDCertain risk factors place patients at greater risk for development of ILD in SSc. These include:

African American15,16

Older age at onset of

SSc17,18

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MORTALITY IN SSc-ILD

In recent years, pulmonary fibrosis/SSc-ILD has become the leading cause of death in patients with SSc.19 Approximately one-third of deaths related to SSc are due to ILD. Deaths due to pulmonary fibrosis increased from 6% to >33% of scleroderma-related deaths from 1972-2001 (P<.001).19

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Causes of SSc-related death between 1972 and 200119 Causes of mortality in SSc (1997-2001)19

Reproduced from Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007;66(7):940-944, Copyright © 2019 with permission from BMJ Publishing Group Ltd.

Renal crisis


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REFERENCES1. Al-Dhaher FF, Pope JE, Ouimet JM. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin Arthritis Rheum. 2010;39(4):269-277. 2. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117(3):557-567. 3. Ramos PS, Silver RM, Fenghali-Bostwick CA. Genetics of systemic sclerosis: recent advances. Curr Opin Rheumatol. 2015;27:521-529. 4. Nicolosi PA, Tombetti E, Maugeri N, Rovere-Querini P, Brunelli S, Manfredi AA. Vascular remodelling and mesenchymal transition in systemic sclerosis. Stem Cells Int. 2016;2016:4636859. 5. Solomon JJ, Olson AL, Fischer A, Bull T, Brown KK, Raghu G. Scleroderma lung disease. Eur Respir Rev. 2013;22(127):6-19. 6. Wells AU, Margaritopoulos GA, Antoniou KM, Denton C. Interstitial lung disease in systemic sclerosis. Semin Respir Crit Care Med. 2014;35(2):213-221. 7. Wollheim FA. Classification of systemic sclerosis. Visions and reality. Rheumatology (Oxford). 2005;44(10):1212-1216. 8. Fan Y, Bender S, Shi W, Shao N, Zoz D. Prevalence and incidence of systemic sclerosis and systemic sclerosis with interstitial lung disease in the US. Poster presented at: AMCP Nexus 2018 Conference; October 24, 2018; Orlando, FL. 9. Ranque B, Mouthon L. Geoepidemiology of systemic sclerosis. Autoimmun Rev. 2010;9(5):A311-A318. 10. Furst DE, Fernandes AW, Iorga SR, Greth W, Bancroft T. Annual medical costs and healthcare resource use in patients with systemic sclerosis in an insured population. J Rheumatol. 2012;39:2303-2309. 11. Varga J. Systemic sclerosis: an update. Bull NYU Hosp Jt Dis. 2008;66(3):198-202. 12. Tan A, Denton CP, Mikhailidis DP, Seifalian AM. Recent advances in the diagnosis and treatment of interstitial lung disease in systemic sclerosis (scleroderma): a review. Clin Exp Rheumatol. 2011;29(2 Suppl 65):S66-S74. 13. Wallace WAH, Fitch PM, Simpson AJ, Howie SEM. Inflammation-associated remodelling and fibrosis in the lung–a process and an end point. Int J Exp Pathol. 2007;88(2):103-110. 14. Scleroderma Foundation. Lung involvement. https://www.scleroderma.org/site/SPageServer/;jsessionid=00000000.app30118b?NONCE_TOKEN=2643A412E0DCBBF90C849F0EA9065ADA&pagename=body_lungheart#.XPxf0C2ZNp8. Accessed July 1, 2019. 15. McNearney TA, Reveille JD, Fischbach M, et al. Pulmonary involvement in systemic sclerosis: associations with genetic, serologic, sociodemographic, and behavioral factors. Arthritis Rheumatol. 2007;57(2):318-326. 16. Steen V, Domsic RT, Lucas M, Fertig N, Medsger TA Jr. A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis. Arthritis Rheumatol. 2012;64(9):2986-2994. 17. Nihtyanova SI, Schreiber BE, Ong VH, et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol. 2014;66(6):1625-1635. 18. Jaeger VK, Wirz EG, Allanore Y, et al. Incidences and risk factors of organ manifestations in the early course of systemic sclerosis: a longitudinal EUSTAR study. PLoS One. 2016;11(10):e0163894. doi:10.1371/journal.pone.0163894. 19. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007;66(7):940-944.


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INDICATIONS• OFEV is indicated for the treatment of

idiopathic pulmonary fibrosis (IPF). • OFEV is indicated to slow the rate of decline

in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

IMPORTANT SAFETY INFORMATIONWARNINGS AND PRECAUTIONSHepatic Impairment: OFEV is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Patients with mild hepatic impairment (Child Pugh A) can be treated with a reduced dosage (100 mg twice daily). Consider treatment interruption or discontinuation for management of adverse reactions. Elevated Liver Enzymes and Drug-Induced Liver Injury• Cases of drug-induced liver injury (DILI)

have been observed with OFEV treatment. In the clinical trials and post-marketing period, non-serious and serious cases of DILI were reported. Cases of severe liver injury with fatal outcome have been reported in the post-marketing period. The majority of hepatic events occur within the first three months of treatment. OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, and GGT) and bilirubin. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases.

• In IPF studies, the majority (94%) of patients with ALT and/or AST elevations had elevations less than 5 times ULN and the majority (95%) of patients with bilirubin elevations had elevations less than 2 times ULN.

• In the SSc-ILD study, a maximum ALT and/or AST greater than or equal to 3 times ULN was observed in 4.9% of patients treated with OFEV.

• Patients with low body weight (less than 65 kg), patients who are Asian, and female

patients may have a higher risk of elevations in liver enzymes. Nintedanib exposure increased with patient age, which may result in increased liver enzymes.

• Conduct liver function tests prior to initiation of treatment, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. Measure liver function tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Dosage modifications, interruption, or discontinuation may be necessary for liver enzyme elevations.

Gastrointestinal DisordersDiarrhea • In IPF studies, diarrhea was the most

frequent gastrointestinal event reported in 62% versus 18% of patients treated with OFEV and placebo, respectively. Events were primarily mild to moderate in intensity and occurred within the first 3 months. Diarrhea led to permanent dose reduction in 11% and discontinuation in 5% of OFEV patients versus 0 and less than 1% in placebo patients, respectively.

• In the SSc-ILD study, diarrhea was the most frequent gastrointestinal event reported in 76% versus 32% of patients treated with OFEV and placebo, respectively. Events were primarily mild to moderate in intensity and occurred within the first 3 months. Diarrhea led to permanent dose reduction in 22% and discontinuation in 7% of OFEV patients versus 1% and 0.3% in placebo patients, respectively.

• Dosage modifications or treatment interruptions may be necessary in patients with diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider treatment interruption if diarrhea continues. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists, discontinue treatment.


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WARNINGS AND PRECAUTIONS (cont’d) Gastrointestinal Disorders (cont’d)Nausea and Vomiting• In IPF studies, nausea was reported in 24%

versus 7% and vomiting was reported in 12% versus 3% of patients treated with OFEV and placebo, respectively. Events were primarily of mild to moderate intensity. Nausea and vomiting led to discontinuation of OFEV in 2% and 1% of patients, respectively.

• In the SSc-ILD study, nausea was reported in 32% versus 14% and vomiting was reported in 25% versus 10% of patients treated with OFEV and placebo, respectively. Events were primarily of mild to moderate intensity. Nausea and vomiting led to discontinuation of OFEV in 2% and 1% of patients, respectively.

• If nausea or vomiting persists despite appropriate supportive care including anti-emetic therapy, consider dose reduction or treatment interruption. OFEV treatment may be resumed at full dosage or at reduced dosage, which subsequently may be increased to full dosage. If severe nausea or vomiting does not resolve, discontinue treatment.

Embryofetal Toxicity: OFEV can cause fetal harm when administered to a pregnant woman and patients should be advised of the potential risk to a fetus. Women should be advised to avoid becoming pregnant while receiving OFEV and to use highly effective contraception during treatment and at least 3 months after the last dose of OFEV. As the impact of nintedanib on the effectiveness of hormonal contraception is unknown, advise women using hormonal contraceptives to add a barrier method. Verify pregnancy status prior to starting OFEV and during treatment as appropriate.

Arterial Thromboembolic Events• In IPF studies, arterial thromboembolic events

were reported in 2.5% of OFEV and 0.8% of placebo patients, respectively. Myocardial infarction was the most common arterial thromboembolic event, occurring in 1.5% of OFEV and 0.4% of placebo patients.

• In the SSc-ILD study, arterial thromboembolic events were reported in 0.7% of patients in both the OFEV-treated and placebo-treated patients. There were 0 cases of myocardial infarction in OFEV-treated patients compared to 0.7% of placebo-treated patients.

• Use caution when treating patients at higher cardiovascular risk, including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.

Risk of Bleeding• OFEV may increase the risk of bleeding. • In IPF studies, bleeding events were reported

in 10% of OFEV versus 7% of placebo patients. In the post-marketing period, non-serious and serious bleeding events, some of which were fatal, have been observed.

• In the SSc-ILD study, bleeding events were reported in 11% of OFEV versus 8% of placebo patients.

• Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.

Gastrointestinal Perforation • OFEV may increase the risk of gastrointestinal

perforation. • In IPF studies, gastrointestinal perforation

was reported in 0.3% of OFEV versus in 0% of placebo patients.

• In the SSc-ILD study, no cases of gastrointestinal perforation were reported in either OFEV or placebo-treated patients.

• In the post-marketing period, cases of gastrointestinal perforations have been reported, some of which were fatal. Use caution when treating patients who have had recent abdominal surgery, have a previous history of diverticular disease, or who are receiving concomitant corticosteroids or NSAIDs. Discontinue therapy with OFEV in patients who develop gastrointestinal perforation. Only use OFEV in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk.


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ADVERSE REACTIONS • Adverse reactions reported in greater than

or equal to 5% of OFEV patients, and more than placebo, included diarrhea, nausea, vomiting, skin ulcer, abdominal pain, liver enzyme elevation, weight decreased, fatigue, decreased appetite, headache, pyrexia, back pain, dizziness and hypertension.

• In IPF studies, the most frequent serious adverse reactions reported in patients treated with OFEV, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in OFEV patients versus placebo were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of OFEV versus 1.8% in placebo patients.

• In the SSc-ILD study, the most frequent serious adverse events reported in patients treated with OFEV, more than placebo, were interstitial lung disease (2.4% vs. 1.7%) and pneumonia (2.8% vs. 0.3%). Within 52 weeks, 5 patients treated with OFEV (1.7%) and 4 patients treated with placebo (1.4%) died. There was no pattern among adverse events leading to death in either treatment arm.

DRUG INTERACTIONS • P-glycoprotein (P-gp) and CYP3A4

Inhibitors and Inducers: Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of potent P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of OFEV. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with OFEV. Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. John’s wort) with OFEV should be avoided as these drugs may decrease exposure to nintedanib.

• Anticoagulants: Nintedanib may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.

USE IN SPECIFIC POPULATIONS• Nursing Mothers: Because of the potential

for serious adverse reactions in nursing infants from OFEV, advise women that breastfeeding is not recommended during treatment.

• Reproductive Potential: OFEV may reduce fertility in females of reproductive potential.

• Smokers: Smoking was associated with decreased exposure to OFEV, which may affect the efficacy of OFEV. Encourage patients to stop smoking prior to and during treatment.

CL-OF-100025 09.06.19


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INDICATIONS AND USAGE1

OFEV® (nintedanib) capsules are indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

OFEV is indicated to slow the rate of decline in pulmonary function in patients with systemic sclerosis–associated interstitial lung disease (SSc-ILD).

DESCRIPTION1

OFEV capsules contain nintedanib, a kinase inhibitor. Nintedanib is presented as the ethanesulfonate salt (esylate), with the chemical name 1H-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino] phenylmethylene]-2-oxo-, methyl ester, (3Z)-, ethanesulfonate (1:1). Its structural formula is shown to the right.

Nintedanib esylate is a bright yellow powder with an empirical formula of C31H33N5O4·C2H6O3S and a molecular weight of 649.76 g/mol.

OFEV capsules for oral administration are available in 2 dose strengths containing 100 mg or 150 mg of nintedanib (equivalent to 120.40 mg or 180.60 mg nintedanib ethanesulfonate, respectively). The inactive ingredients of OFEV are the following: fill material: triglycerides, hard fat, and lecithin; capsule shell: gelatin, glycerol, titanium dioxide, red ferric oxide, yellow ferric oxide, and black ink.

H3C H3C

H3C

O

O

NH

O

OOO

N NCH3N

S

O

NH

PRODUCT DESCRIPTION


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PRODUCT DESCRIPTION (cont’d)DOSAGE AND ADMINISTRATIONTesting prior to OFEV® (nintedanib) capsules administration1

Conduct liver function tests in all patients and a pregnancy test in females of reproductive potential prior to initiating treatment with OFEV.

Recommended dosage1

The recommended dosage of OFEV is 150 mg twice daily administered approximately 12 hours apart. OFEV capsules should be taken with food and swallowed whole with liquid. OFEV capsules should not be chewed or crushed because of a bitter taste. The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known.

If a dose of OFEV is missed, the next dose should be taken at the next scheduled time. Advise the patient not to make up for a missed dose. Do not exceed the recommended maximum daily dosage of 300 mg.

In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg twice daily approximately 12 hours apart taken with food.

Recommended testing1

• Conduct liver function tests (alanine transaminase [AST], aspartate transaminase [AST], and bilirubin) in all patients prior to initiation of treatment with OFEV, at regular intervals during the first 3 months of treatment, and periodically thereafter or as clinically indicated

• Measure liver function tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice

• Dosage modifications or interruption may be necessary for liver enzyme elevations• Conduct a pregnancy test in females of reproductive potential prior to initiating treatment

with OFEV

Dosage modification due to adverse reactions1

In addition to symptomatic treatment, if applicable, the management of adverse reactions of OFEV may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy. OFEV treatment may be resumed at the full dosage (150 mg twice daily) or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If a patient does not tolerate 100 mg twice daily, discontinue treatment with OFEV.

Dose modifications or interruptions may be necessary for liver enzyme elevations. Conduct liver function tests (AST, ALT, and bilirubin) prior to initiation of treatment with OFEV, at regular intervals during the first 3 months of treatment, and periodically thereafter or as clinically indicated. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Discontinue OFEV in patients with AST or ALT greater than 3 times the upper


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StorageStore at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Protect from exposure to high humidity and avoid excessive heat. If repackaged, use USP tight container. Keep out of reach of children.

Not shown at actual size

Bottles of 60 NDC: 0597-0145-60

Not shown at actual size

DOSAGE AND ADMINISTRATION (cont’d)Dosage modification due to adverse reactions1 (cont’d)limit of normal (ULN) with signs or symptoms of liver injury and for AST or ALT elevations greater than 5 times the upper limit of normal. For AST or ALT greater than 3 times to less than 5 times the ULN without signs of liver damage, interrupt treatment or reduce OFEV® (nintedanib) capsules to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with OFEV may be reintroduced at a reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage (150 mg twice daily).

In patients with mild hepatic impairment (Child Pugh A), consider treatment interruption or discontinuation for management of adverse reactions.

HOW SUPPLIED/STORAGE AND HANDLING1

150 mg: brown, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and “150.” They are packaged in high-density polyethylene (HDPE) bottles with a child-resistant closure, available as follows:

100 mg: peach, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and “100.” They are packaged in HDPE bottles with a child-resistant closure, available as follows:

PRODUCT DESCRIPTION (cont’d)

Bottles of 60 NDC: 0597-0143-60


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REFERENCE

1. OFEV® (nintedanib) Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2019.


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CLINICAL PHARMACOLOGYMECHANISM OF ACTION1

Nintedanib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) and nonreceptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) α and ß, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, colony stimulating factor 1 receptor (CSF1R), and Fms-like tyrosine kinase-3 (FLT-3). These kinases except for FLT-3 have been implicated in pathogenesis of interstitial lung diseases (ILD). Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these kinases and blocks the intracellular signaling cascades, which have been demonstrated to be involved in the pathogenesis of fibrotic tissue remodeling in ILD. Nintedanib also inhibits the following nRTKs: Lck, Lyn and Src kinases. The contribution of FLT-3 and nRTK inhibition to nintedanib efficacy in ILD is unknown.

PHARMACODYNAMICS1 Cardiac electrophysiologyIn a study in patients with renal cell cancer, QT/QTc measurements were recorded and showed that a single oral dose of 200-mg nintedanib, as well as multiple oral doses of 200-mg nintedanib administered twice daily for 15 days, did not prolong the QTcF interval.

PHARMACOKINETICS1

The pharmacokinetic (PK) properties of nintedanib were similar in healthy volunteers, patients with IPF, patients with SSc-ILD, and patients with cancer. The PK of nintedanib is linear. Dose proportionality was shown by an increase of nintedanib exposure with increasing doses (dose range 50 to 450 mg once daily and 150 to 300 mg twice daily). Accumulation upon multiple administrations in patients with IPF was 1.76-fold for area under the curve (AUC). Steady-state plasma concentrations were achieved within 1 week of dosing. Nintedanib trough concentrations remained stable for more than 1 year. The interindividual variability in the PK of nintedanib was moderate to high (coefficient of variation of standard PK parameters in the range of 30% to 70%), and the intraindividual variability was low to moderate (coefficients of variation below 40%).

AbsorptionNintedanib reached maximum plasma concentrations approximately 2 to 4 hours after oral administration as a soft gelatin capsule under fed conditions. The absolute bioavailability of a 100-mg dose was 4.7% (90% confidence interval [CI]=6.08) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.After food intake, nintedanib exposure increased by approximately 20% compared with administration under fasted conditions (90% CI=95.3% to 152.5%), and absorption was delayed (median time to maximum concentration, fasted: 2.00 hours; fed: 3.98 hours), regardless of the food type.


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CLINICAL PHARMACOLOGY (cont’d)PHARMACOKINETICS1 (cont’d)Distribution Nintedanib follows biphasic disposition kinetics. After intravenous infusion, a high volume of distribution, which was larger than total body volume (Vss: 1050 L), was observed.

The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood-to-plasma ratio of 0.87.

EliminationThe effective half-life of nintedanib in patients with IPF was 9.5 hours (percent coefficient of variation for geometric mean [gCV] 31.9%). Total plasma clearance (CL) after intravenous infusion was high (CL: 1390 mL/min; gCV 28.8%). Urinary excretion of unchanged drug within 48 hours was about 0.05% of the dose after oral and about 1.4% of the dose after intravenous administration; the renal clearance was 20 mL/min.

MetabolismThe prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by glucuronosyltransferase (UGT) enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. Only a minor extent of the biotransformation of nintedanib consisted of cytochrome P (CYP) pathways, with CYP3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human absorption, distribution, metabolism, and elimination study. In vitro, CYP-dependent metabolism accounted for about 5% compared with about 25% ester cleavage.

ExcretionThe major route of elimination of drug-related radioactivity after oral administration of [14C] nintedanib was via fecal/biliary excretion (93.4% of dose), and the majority of nintedanib was excreted as BIBF 1202. The contribution of renal excretion to the total clearance was low (0.65% of dose). The overall recovery was considered complete (above 90%) within 4 days after dosing.

Specific populationsAge, body weight, and sexBased on population PK analysis, age and body weight were correlated with nintedanib exposure. However, the effects on exposure are not sufficient to warrant a dose adjustment. There was no influence of sex on the exposure of nintedanib.

Renal impairmentBased on a population PK analysis of data from 933 patients with IPF, exposure to nintedanib was not influenced by mild (creatinine clearance [CrCl]: 60 mL/min to 90 mL/min; n=399) or moderate (CrCl: 30 mL/min to 60 mL/min; n=116) renal impairment. Data in severe renal impairment (CrCl below 30 mL/min) were limited.


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CLINICAL PHARMACOLOGY (cont’d)PHARMACOKINETICS1 (cont’d)Hepatic impairmentA dedicated single-dose phase 1 pharmacokinetics study of OFEV® (nintedanib) capsules compared 8 subjects with mild hepatic impairment (Child Pugh A) and 8 subjects with moderate hepatic impairment (Child Pugh B) to 17 subjects with normal hepatic function. In subjects with mild hepatic impairment, the mean exposure to nintedanib was 2.4-fold higher based on maximum plasma concentration (Cmax ; 90% CI=1.6 to 3.6) and 2.2-fold higher based on AUC from time 0 to infinity (AUC0-inf; 90% CI=1.4 to 3.5). In subjects with moderate hepatic impairment, exposure was 6.9-fold higher based on Cmax (90% CI=4.4 to 11.0) and 7.6-fold higher based on AUC0-inf (90% CI=5.1 to 11.3). Subjects with severe hepatic impairment (Child Pugh C) have not been studied.

SmokersIn the population PK analysis, the exposure of nintedanib was 21% lower in current smokers compared with ex-smokers and never-smokers. The effect is not sufficient to warrant a dose adjustment.

Drug interaction studiesPotential for nintedanib to affect other drugsEffect of nintedanib coadministration on pirfenidone AUC and Cmax was evaluated in a multiple-dose study. Nintedanib did not have an effect on the exposure of pirfenidone.In in vitro studies, nintedanib was shown not to be an inhibitor of organic anion-transporting polypeptide (OATP)-1B1, OATP-1B3, OATP-2B1, organic cation transporter (OCT)-2, or multidrug resistance-associated protein 2 (MRP-2). In vitro studies also showed that nintedanib has weak inhibitory potential on OCT-1, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp); these findings are considered to be of low clinical relevance. Nintedanib and its metabolites, BIBF 1202 and BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in vitro.

Potential for other drugs to affect nintedanibNintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with the P-gp and CYP3A4 inhibitor ketoconazole increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on Cmax in a dedicated drug-drug interaction study. In a drug-drug interaction study with the P-gp and CYP3A4 inducer rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on Cmax upon coadministration with rifampicin compared with administration of nintedanib alone.Effect of pirfenidone coadministration on nintedanib AUC and Cmax was evaluated in a multiple-dose drug-drug interaction study. Pirfenidone did not have an effect on the exposure of nintedanib. Concomitant treatment with nintedanib and pirfenidone was also investigated in a separate trial, which was an exploratory open-label, randomized (1:1) trial of nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times a day) compared to nintedanib 150 mg twice daily alone in 105 randomized patients for 12 weeks. Similar nintedanib trough plasma concentrations were observed when comparing patients receiving nintedanib alone with patients receiving nintedanib with add-on pirfenidone.Healthy volunteers received a single dose of 150 mg nintedanib before and after multiple dosing of 125 mg bosentan twice daily at steady state. Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib.


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CLINICAL PHARMACOLOGY (cont’d)PHARMACOKINETICS1 (cont’d)Nintedanib displays a pH-dependent solubility profile with increased solubility at acidic pH <3. However, in the clinical trials, coadministration with proton pump inhibitors or histamine H2 antagonists did not influence the exposure (trough concentrations) of nintedanib.In in vitro studies, nintedanib was shown not to be a substrate of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, MRP-2, or BCRP. In vitro studies also showed that nintedanib was a substrate of OCT-1; these findings are considered to be of low clinical relevance.


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REFERENCE

1. OFEV® (nintedanib) Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2019.


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CLINICAL EFFICACYIPFCLINICAL STUDIES DESCRIPTION1

The clinical efficacy of OFEV® (nintedanib) capsules has been studied in 1231 patients with IPF in one phase 2 (TOMORROW) and two phase 3 studies (INPULSIS®-1 and INPULSIS®-2). These were randomized, double-blind, placebo-controlled studies comparing treatment with OFEV 150 mg twice daily to placebo for 52 weeks.

INPULSIS®-1 and INPULSIS®-2 were identical in design, and TOMORROW was very similar in design. Patients were randomized in a 3:2 ratio (1:1 for TOMORROW) to either OFEV 150 mg or placebo twice daily for 52 weeks. TOMORROW also included other treatment arms (50 mg daily, 50 mg twice daily, and 100 mg twice daily) that are not further discussed. The primary endpoint was the annual rate of decline in forced vital capacity (FVC). Time to first acute IPF exacerbation was a key secondary endpoint in INPULSIS®-1 and INPULSIS®-2 and a secondary endpoint in TOMORROW. Change from baseline in FVC percent predicted and survival were additional secondary endpoints in all studies.

Patients were required to have a diagnosis of IPF (ATS/ERS/JRS/ALAT criteria) for <5 years. Diagnoses were centrally adjudicated based on radiologic and, if applicable, histopathologic confirmation. Patients were required to be ≥40 years of age with an FVC ≥50% of predicted and a carbon monoxide diffusing capacity (DLCO, corrected for hemoglobin) 30% to 79% of predicted. Patients with relevant airway obstruction (ie, prebronchodilator forced expiratory volume in 1 second [FEV1]/FVC <0.7) or, in the opinion of the investigator, likely to receive a lung transplant during the studies were excluded (being listed for lung transplant was acceptable for inclusion). Patients with >1.5 times ULN of ALT, AST, or bilirubin; patients with a known risk or predisposition to bleeding; patients receiving a full dose of anticoagulation treatment; and patients with a recent history of myocardial infarction or stroke were excluded from the studies. Patients were also excluded if they received other investigational therapy, azathioprine, cyclophosphamide, or cyclosporine A within 8 weeks of entry into this trial, or n-acetylcysteine and prednisone (>15 mg/day or equivalent) within 2 weeks. The majority of patients were white or Asian (60% and 30%, respectively) and male (79%). Patients had a mean age of 67 years and a mean FVC percent predicted of 80%.


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CLINICAL EFFICACY (cont’d)

IPF (cont'd)CLINICAL STUDIES DESCRIPTION (cont’d)The patient population was similar across clinical trials.1-4 The table below outlines the key demographic and baseline characteristics of patients taking OFEV® (nintedanib) capsules or placebo in the 3 trials.

SD=standard deviation.

ANNUAL RATE OF DECLINE IN FVC1

A statistically significant reduction in the annual rate of decline of FVC (in mL) was demonstrated in patients receiving OFEV compared with patients receiving placebo based on the random coefficient regression model, adjusted for gender, height, and age. The treatment effect on FVC was consistent in all 3 studies. See the table at the top of the next page for individual study results.

Key demographics and baseline patient characteristics1-4


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The figure below displays the change from baseline over time in both treatment groups for the 3 clinical trials. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all time points through week 52.

Treatment arms diverged at all time points through 52 weeks in 3 clinical trials1

a Randomized set in TOMORROW; treated set in INPULSIS®-1 and -2.bEstimated based on a random coefficient regression model.

Annual rate of decline in FVC (mL) in INPULSIS®-1, INPULSIS®-2, and TOMORROW with OFEV® (nintedanib) capsules1,3,4,a

cMean change from baseline at 52 weeks was calculated from values at baseline and at 52 weeks.3 dAdjusted mean difference at week 52 based on mixed model for repeated measures between OFEV (–95 mL) vs placebo (–205 mL).3

e Mean change from baseline at day 365 was calculated from values at baseline and at day 365.4

IPF (cont'd)ANNUAL RATE OF DECLINE IN FVC (cont’d)

INPULSIS®-11,3 INPULSIS®-21,3TOMORROW1,4

83

-191

204

-240

84

-60

131

(27, 235)

309

-115

125

(78, 173)

329

-114

94

(45, 143)

219

-207

OFEV 150 mg twice daily

OFEV 150 mg twice daily

OFEV 150 mg twice dailyPlacebo Placebo Placebo

Number of analyzed patients

Ratea of decline over 52 weeks, mL/year

Comparison vs placebo di�erenceb

95% CI

TOMORROW1,2,4,eINPULSIS®-1 and INPULSIS®-21,3,c

Placebo (n=217)

P<.001 (95% CI=70.9, 148.6)d

INPULSIS®-2

OFEV (n=327)

P<.001 (95% CI=71.3, 148.6)c

INPULSIS®-1

Placebo (n=204)OFEV (n=307)

522 4 6 12 24 36

Weeks

–240

–210

–120

30

–30

–60

–90

–180

–150

0

Mea

n ob

serv

ed c

hang

e fr

om b

asel

ine

in F

VC, m

L

0

Placebo (n=87)

OFEV 150 mg bid(n=86)

250 300 3500 50 100 150 200

Days

–240

–210

–120

30

–30

–60

–90

–180

–150

0

Me

an

ob

serv

ed

ch

an

ge

fr

om

ba

selin

e in

FV

C, m

L


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CLINICAL EFFICACY (cont’d)IPF (cont'd)CHANGE FROM BASELINE IN PERCENT PREDICTED FVC The figure below presents the cumulative distribution for all cutoffs for the change from baseline in FVC percent predicted at week 52 for INPULSIS®-1. For all categorical declines in lung function, the proportion of patients declining was lower on OFEV® (nintedanib) capsules than on placebo.

Cumulative distribution of patients by change in percent predicted FVC from baseline to week 52 in INPULSIS®-1.a The vertical lines indicate ≥0% decline or ≥10% decline in percent predicted FVC1

• INPULSIS®-2 showed similar results

INPULSIS®-1

Placebo (n=204)OFEV (n=309)

0

–10 –5 0 5 15 20 25 30

10

20

30

40

50

60

70

80

90

100

Improvement in FVC Decline in FVC

Patie

nts,

%

Absolute change in percent predicted FVC from baseline to week 52, %

43%

10

29%

82%

70%

a Missing data for change from baseline at week 52 in percent predicted FVC (due to death, lost to follow-up, or censoring before 52 weeks) were imputed using the worst decline from baseline at week 52 observed among all patients with available data, regardless of treatment.1


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CLINICAL EFFICACY (cont’d)IPF (cont'd)TIME TO FIRST ACUTE IPF EXACERBATION1

Acute IPF exacerbation was defined as unexplained worsening or development of dyspnea within 30 days, new diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal abnormalities with no pneumothorax or pleural effusion, and exclusion of alternative causes. Acute IPF exacerbation was adjudicated in INPULSIS®-1 and -2. In TOMORROW (investigator reported) and INPULSIS®-2 (adjudicated), the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving OFEV® (nintedanib) capsules compared with placebo (hazard ratio [HR]=0.16, 95% CI=0.04, 0.71) and (HR=0.20, 95% CI=0.07, 0.56), respectively. In INPULSIS®-1 (adjudicated), there was no difference between the treatment groups (HR=0.55, 95% CI=0.20, 1.54).

SURVIVAL ANALYSIS1

Survival was evaluated for OFEV compared with placebo in INPULSIS®-1 and INPULSIS®-2 as an exploratory analysis to support the primary endpoint (FVC). All-cause mortality was assessed over the study duration and available follow-up period, regardless of cause of death and whether patients continued treatment. All-cause mortality did not show a statistically significant difference. (See figure below.)

Kaplan-Meier estimates of all-cause mortality at vital status — end of study: INPULSIS®-1 and INPULSIS®-21

Time to death over 52 weeks (days)

1800 30 60 90 120 150 373210 240 270 300 330 360

HR=0.70 (95% CI=0.43, 1.12)

Kapl

an-M

eier

est

imat

e of

sur

viva

l, %

OFEV 150 mg bidPlacebo

Censored

No. at risk

OFEVPlacebo

638 637 635 632 628 623 620 619 617 612 606 601 591 532423 422 420 418 418 416 414 408 406 403 400 394 388 358

0

100

90

80

70

60

50


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SSc-ILD CLINICAL STUDY DESCRIPTION The clinical efficacy of OFEV® (nintedanib) capsules has been studied in patients with SSc-ILD in SENSCIS®, a randomized, double-blind, placebo-controlled phase 3 trial. A total of 580 patients were randomized in a 1:1 ratio to receive either OFEV 150 mg twice daily or matching placebo for at least 52 weeks, of which 576 patients were treated. Randomization was stratified by anti-topoisomerase antibody (ATA) status. Individual patients remained on blinded trial treatment for up to 100 weeks. The primary endpoint was the annual rate of decline in FVC over 52 weeks. The absolute change from baseline in the modified Rodnan skin score (mRSS) at Week 52 was a key secondary endpoint. Mortality over the whole trial was an additional secondary endpoint.1

Patients were diagnosed with SSc-ILD based upon the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc with onset of disease (first non-Raynaud symptom) of less than 7 years and greater than or equal to 10% fibrosis on a chest HRCT scan conducted within the previous 12 months. Patients were required to have an FVC greater than or equal to 40% of predicted and a DLCO 30% to 89% of predicted. Patients with relevant airways obstruction (ie, pre-bronchodilator FEV1 /FVC less than 0.7) or previous or planned hematopoietic stem cell transplant were excluded from the trial. Patients with greater than 1.5 times ULN of ALT, AST, or bilirubin, patients with a known risk or predisposition to bleeding, patients receiving a full dose of anticoagulation treatment, and patients with a recent history of myocardial infarction or stroke were excluded from the study. Patients were excluded if they had significant pulmonary hypertension, more than three digital fingertip ulcers, a history of severe digital necrosis requiring hospitalization, or a history of scleroderma renal crisis. Patients were also excluded if they received other investigational therapy, previous treatment with nintedanib or pirfenidone, azathioprine within 8 weeks prior to randomization, or cyclophosphamide or cyclosporine A within 6 months prior to randomization.1

The SENSCIS® trial population was representative of SSc-ILD patients seen in clinical practice, as presented in the table below.

CLINICAL EFFICACY

53.4 (12.6)73.6 64.6 28.1 5.6

2541 (816)72.7 (16.6)53.2 (15.1)35.2 (20.7)

3.5 (0.4, 7.2)50.7 49.3 61.5

48.6 5.2

Placebo (n=288)

54.6 (11.8)76.7 69.8 21.5 6.9

2459 (736)72.4 (16.8)52.9 (15.1)36.8 (21.8)

3.4 (0.3, 7.1)53.1 46.9 60.1

48.3 8.0

Key demographics and baseline characteristics5

OFEV (n=288)


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IEW The annual rate of decline of FVC (in mL) over 52 weeks was significantly reduced by 41 mL/yr in

patients receiving OFEV compared to patients receiving placebo, corresponding to a relative treatment effect of 44%. See table below.1

Annual rate of decline in FVC (mL) in SENSCIS®1

The figure below displays the change from baseline over time in both treatment groups. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all time points through Week 52. Separation of the mean values is seen after 12 weeks of treatment.1


SSc-ILD (cont'd) ANNUAL RATE OF DECLINE IN FVC

Number of patients

Mea

n ab

solu

te c

hang

e fr

om

bas

elin

e in

FV

C (

mL)

Week

Placebo

OFEV

278273281283288

20 4 6 12 24 36 52

-140

-120

-100

-80

-60

-40

-20

0

20

PlaceboOFEV 280281283288 283

278283

262268

241257

Mean observed FVC change from baseline (mL) over time1

PlaceboOFEV 150 mg twice daily

287

-52

41 mL/yr

(3, 79)

288

-93

Number of analyzed patients

Rate of decline over 52 weeks

Comparison vs placebo di�erencea

95% CI

a Based on a random coefficient regression model, adjusted for gender, height, age, ATA status, FVC at baseline, and FVC at baseline-by-time.


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Subgroup analyses of the mean treatment difference in FVC (mL) decline at week 52 by region and mycophenolate use (SENSCIS®)1

288ALL

No

YesMycophenolate use at baseline

Region

Placebo

N NRate ofDecline

Rate ofDecline

Di�erence [95% CI]

Nintedanib 150 bid

Asia

Europe

Canada and United States

Rest of World

-93 -52287 41 [3; 79]

148 -119 -64149 55 [2; 109]

73 -52 -4269 10 [-66; 86]

126 -107 -67139 40 [-17; 96]

71 -92 -4859 43 [-37; 124]

140 -67 -40138 26 [-28; 81]

18 -176 220 178 [28; 329]

Favors Placebo

-50 0 50 100 150 200

Favors Nintedanib 150 bid

-100


SSc-ILD (cont'd) ANNUAL RATE OF DECLINE IN FVC (cont'd)In two prespecified subgroup efficacy analyses, the mean treatment difference in FVC decline at 52 weeks in patients was examined by region and mycophenolate use. See figures below.1


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No benefit in mRSS was observed in patients receiving OFEV. The adjusted mean absolute change from baseline in mRSS at Week 52 was comparable between the OFEV group (-2.17 [95% CI: -2.69, -1.65]) and the placebo group (-1.96 [95% CI: -2.48, -1.45]). The adjusted mean difference between the treatment groups was -0.21 (95% CI: -0.94, 0.53).1

SURVIVALNo difference in survival was observed in an exploratory analysis of mortality over the whole trial (OFEV: n=10 [3.5%] vs placebo: n=9 [3.1%]). The analysis of time to death over the whole trial resulted in a hazard ratio of 1.16 (95% CI: 0.47, 2.84).1

MODIFIED RODNAN SKIN SCORE (mRSS)

CLINICAL EFFICACY (cont’d)SSc-ILD (cont'd)CHANGE FROM BASELINE IN PERCENT PREDICTED FVC1,2,5

The figure below presents the percent change from baseline in FVC in mL at Week 52 for SENSCIS®. For the majority of patients, the decline in lung function was less on OFEV® (nintedanib) capsules than on placebo.1

Histogram of the percent change in FVC (mL) from baseline to week 52 according to treatment and percent increments or decrements of 5 mL (SENSCIS®)

aPatients classified as having missing FVC data at Week 52 are those with no FVC assessment between Day 310 and Day 373.

38% had improvement26% had improvement

Placebo

[35,55)

[30,35)

[25,30)

[20,25)

[15,20)

[10,15)

[5,10)

[0,5)

[-5,0)

[-10,-5)

[-15,-10)

Per

cent

Cha

nge

fro

m B

asel

ine

in F

VC

(m

L) a

t W

eek

52

[-20,-15)

[-25,-20)

[-30,-25)

[-35,-30)

[-40,-35)

25 20 15 10 5 0

1%

1%1%

11% 16%

1%

2% 2%

2%

6%

13%

11%

4%2%

7%

17%

25%

22%

1%

22%

21%

5 %

7 %

Proportion (%)

Nintedanib 150bid

Placebo

5 10 15 20 25

Missinga

Nintedanib 150 bid

62% had worsening or missing74% had worsening or missing


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REFERENCES1. OFEV® (nintedanib) Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2019. 2. Data on file. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 3. Richeldi L, du Bois RM, Raghu G, et al; for the INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082. 4. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079-1087. 5. Distler O, Highland KB, Gahlemann AM, et al; SENSCIS Trial Investigators. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380(26):2518-2528.


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SAFETY PROFILECLINICAL STUDIES EXPERIENCEBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.1

The safety of OFEV® (nintedanib) capsules was evaluated in over 1000 IPF patients and over 280 patients with SSc-ILD. Over 200 IPF patients were exposed to OFEV for more than 2 years in clinical trials.1

IPFOFEV was studied in patients with IPF in 3 randomized, double-blind, placebo-controlled, 52-week trials. The safety was further supported in a long-term extension trial and a postmarketing surveillance analysis.1-3 In the phase 2 (TOMORROW) and phase 3 (INPULSIS®-1 and INPULSIS®-2) trials, 723 patients with IPF received OFEV 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with OFEV and 11 months for patients treated with placebo. Subjects ranged in age from 42 to 89 years (median age: 67 years). Most patients were male (79%) and white (60%).1

The most frequent serious adverse reactions reported in the first 3 clinical trials in patients treated with OFEV, more than placebo, were bronchitis (1.2% vs 0.8%) and myocardial infarction (1.5% vs 0.4%). The most common adverse events (AEs) leading to death in patients treated with OFEV, more than placebo, were pneumonia (0.7% vs 0.6%), lung neoplasm malignant (0.3% vs 0%), and myocardial infarction (MI) (0.3% vs 0.2%). In the predefined category of major adverse cardiovascular events (MACE), including MI, fatal events were reported in 0.6% of OFEV-treated patients and 1.8% of placebo-treated patients.1

Adverse reactions leading to permanent dose reductions were reported in 16% of OFEV-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with OFEV was diarrhea (11%).1

Adverse reactions leading to discontinuation were reported in 21% of patients who received OFEV and 15% of patients who received placebo. The most common adverse reactions that led to discontinuation in OFEV-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%).1

The most common adverse reactions with an incidence of ≥5% and more frequent in the OFEV than placebo treatment group are listed in the table on the next page.


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IPF (cont'd)CLINICAL STUDIES EXPERIENCE (cont’d)Adverse reactions occurring in ≥5% of patients treated with OFEV® (nintedanib) capsules and more commonly than placebo in TOMORROW, INPULSIS®-1, and INPULSIS®-21

SAFETY PROFILE (cont’d)

Diarrhea

Nausea

Abdominal pain

Vomiting

Liver enzyme elevations

Decreased appetite

Headache

Weight decreased

Hypertension

Placebo(n=508)

18%

7%

6%

3%

3%

5%

5%

3%

4%

OFEV(n=723)

62%

24%

15%

12%

14%

11%

8%

10%

5%

• In addition, hypothyroidism was reported in more patients who received OFEV rather than placebo (1.1% vs 0.6%)1

• The most common AEs were gastrointestinal in nature and generally of mild or moderate intensity1

95% of diarrhea events were

mild or moderate in intensity1,4

The majority of diarrhea events occurred within the first 3 months of

treatment1

5% of all patients studied discontinued treatment because of

diarrhea events1


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Arterial thromboembolic eventsd

MACEe

MACE leading to death

Placebo (n=508), % (n)

OFEV (n=723), % (n)

3.6% (26) 3.5% (18)

0.8% (4)

1.8% (9)0.6% (4)

2.5% (18)

AE cardiac disordersb

Serious AE Fatal AE Ischemic heart disease MI MI leading to death Other ischemic heart diseasec


OFEV®(nintedanib) capsules (n=723), % (n)

9.7% (70)4.6% (33)0.4% (3)4.0% (29)1.5% (11)0.3% (2)1.5% (11)

10.8% (55)5.9% (30)1.8% (9)3.7% (19)0.4% (2)0.2% (1)3.0% (15)

aRandomization was 3:2 in the INPULSIS® trials and 1:1 in the TOMORROW trial for OFEV:placebo.1,4,6

b AE cardiac disorders include all AEs that primarily affected the cardiac system (including, but not limited to, ischemic heart disease, congestive heart failure, and cardiac arrhythmia).5

c Other ischemic heart disease includes the preferred terms coronary artery disease, angina pectoris, coronary artery stenosis, coronary angioplasty, coronary arterial stent insertion, electrocardiogram ST segment depression, angina unstable, and myocardial ischemia.5

d Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of OFEV-treated patients compared with 0.4% of placebo-treated patients.1

e The category of MACE comprised the following: AEs leading to death from cardiac disorders and vascular disorders; any AEs due to ischemic heart disease; any stroke (based on an internal Boehringer Ingelheim definition); and the preferred terms sudden death, cardiac death, sudden cardiac death, nonfatal acute myocardial infarction, myocardial infarction, and coronary artery occlusion.5

Use caution when treating patients at higher cardiovascular risk, including those with known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.1

SAFETY PROFILE (cont’d)IPF (cont'd)ADDITIONAL SAFETY DATA

Cardiac AEs observed in clinical trials5,a

Cardiovascular AEs observed in clinical trials1,5,a


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Total bleeding events Epistaxis Contusion Rectal hemorrhage Hemoptysis



9.5% (69)3.7% (27)1.4% (10)1.1% (8)0.8% (6)

7.3% (37)3.0% (15)0.8% (4)1.0% (5)1.4% (7)


• Other reported bleeding events with OFEV compared with placebo, respectively, included hematuria (0.4% vs 0.8%), cystitis hemorrhagic (0.3% vs 0%), diarrhea hemorrhagic (0.3% vs 0%), gastrointestinal hemorrhage (0.3% vs 0%), hematoma (0.3% vs 0%), purpura (0.3% vs 0%), aortic aneurysm rupture (0.1% vs 0%), aortic intramural hematoma (0.1% vs 0%), blood urine present (0.1% vs 0.2%), catheter site hematoma (0.1% vs 0%), conjunctival hemorrhage (0.1% vs 0%), ecchymosis (0.1% vs 0%), hematemesis (0.1% vs 0%), hematochezia (0.1% vs 0.6%), hemorrhage (0.1% vs 0%), incision site hemorrhage (0.1% vs 0%), metrorrhagia (0.1% vs 0%), petechiae (0.1% vs 0%), post-procedural hemorrhage (0.1% vs 0%), uterine hemorrhage (0.1% vs 0%), vessel puncture site hemorrhage (0.1% vs 0%), bone contusion (0% vs 0.2%), intestinal hemorrhage (0% vs 0.2%), melena (0% vs 0.4%), and vessel puncture site hematoma (0% vs 0.2%)

• In the postmarketing period, nonserious and serious bleeding events, some of which were fatal, have been observed

• Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk1

Bleeding events observed in clinical trials5

IPF (cont'd)ADDITIONAL SAFETY DATA (cont’d)


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Liver enzyme and bilirubin elevations observed in clinical trials5

Maximum ALT ≥3 ULN ≥5 ULN ≥8 ULNMaximum AST ≥3 ULN ≥5 ULN ≥8 ULNMaximum AST and/or ALT ≥3 ULN ≥5 ULN ≥8 ULNMaximum total bilirubin ≥1.5 ULN ≥2 ULN

Placebo(n=508), % (n)

0.6% (3)0.0% (0)0.0% (0)

0.2% (1)0.2% (1)0.2% (1)

0.6% (3)0.2% (1)0.2% (1)

0.8% (4)0.4% (2)


4.1% (30)1.4% (10)0.6% (4)

3.2% (23)1.1% (8)0.6% (4)

5.0% (36)1.9% (14)0.7% (5)

2.1% (15)0.4% (3)

• Cases of drug-induced liver injury (DILI) have been observed with OFEV treatment. In the clinical trials and postmarketing period, non-serious and serious cases of DILI were reported. Cases of severe liver injury with fatal outcome have been reported in the postmarketing period. The majority of hepatic events occur within the first 3 months of treatment. In clinical trials, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT) and bilirubin. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases. In IPF studies (TOMORROW. INPULSIS®-1, and INPULSIS®-2), the majority (94%) of patients with ALT and/or AST elevations had elevations less than 5 times ULN and the majority (95%) of patients with bilirubin elevations had elevations less than 2 times ULN. In the SSc-ILD study (SENSCIS®), a maximum ALT and/or AST greater than or equal to 3 times ULN was observed for 4.9% of patients in the OFEV group and for 0.7% of patients in the placebo group. Patients with a low body weight (less than 65 kg), Asian, and female patients may have a higher risk of elevations in liver enzymes. Nintedanib exposure increased with patient age, which may also result in a higher risk of increased liver enzymes.

• Conduct liver function tests (ALT, AST, and bilirubin) in all patients prior to initiation of treatment with OFEV, at regular intervals during the first 3 months of treatment, and periodically thereafter or as clinically indicated. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Dosage modifications or interruption may be necessary for liver enzyme elevations

IPF (cont'd)ADDITIONAL SAFETY DATA (cont’d)


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IPF (cont'd)OVERDOSAGE1

In IPF trials, 1 patient was inadvertently exposed to a dose of 600 mg daily for a total of 21 days. A nonserious AE (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of other reported events. Overdose was also reported in 2 patients in oncology studies who were exposed to a maximum of 600 mg twice daily for up to 8 days. Adverse events reported were consistent with the existing safety profile of OFEV. Both patients recovered. In case of overdose, interrupt treatment and initiate general supportive measures as appropriate.

SSc-ILDCLINICAL STUDY EXPERIENCE1

OFEV was studied in SENSCIS®, a phase 3, randomized, double-blind, placebo-controlled trial, in which 576 patients with SSc-ILD received OFEV 150 mg twice daily (n=288) or placebo (n=288) for at least 52 weeks. Individual patients were treated for up to 100 weeks. The median duration of exposure was 15 months for patients treated with OFEV and 16 months for patients treated with placebo. Subjects ranged in age from 20 to 79 years (median age of 55 years). Most patients were female (75%). Patients were mostly white (67%), Asian (25%), or black (6%). At baseline, 49% of patients were on stable therapy with mycophenolate.

The most frequent serious adverse events reported in patients treated with OFEV, more than placebo, were interstitial lung disease (2.4% nintedanib vs. 1.7% placebo) and pneumonia (2.8% nintedanib vs. 0.3% placebo). Within 52 weeks, 5 patients treated with OFEV (1.7%) and 4 patients treated with placebo (1.4%) died. There was no pattern among adverse events leading to death in either treatment arm.

Adverse reactions leading to permanent dose reductions were reported in 34% of OFEV-treated patients and 4% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with OFEV was diarrhea (22%).

Adverse reactions leading to discontinuation were reported in 16% of OFEV-treated patients and 9% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in OFEV-treated patients were diarrhea (7%), nausea (2%), vomiting (1%), abdominal pain (1%), and interstitial lung disease (1%).

The safety profile in patients treated with OFEV with or without mycophenolate at baseline was comparable.


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Adverse reactions occurring in ≥5% of OFEV-treated patients and more commonly than placebo in SENSCIS®1

aIncludes abdominal pain, abdominal pain upper, abdominal pain lower, and esophageal pain.b Includes alanine aminotransferase increased, gamma-glutamyltransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, blood alkaline phosphatase increased, transaminase increased, and hepatic function abnormal.

cIncludes hypertension, blood pressure increased, and hypertensive crisis.

SAFETY PROFILE (cont’d)SSc-ILD (cont'd)CLINICAL STUDY EXPERIENCE (cont'd)The most common adverse reactions with an incidence of greater than or equal to 5% in OFEV-treated patients and more commonly than in placebo are listed in the table below.

Adverse Reaction OFEV 150 mg n=288

Placebo n=288

Diarrhea 76% 32%

Nausea 32% 14%

Vomiting 25% 10%

Skin ulcer 18% 17%

Abdominal paina 18% 11%

Liver enzyme elevationb 13% 3%

Weight decreased 12% 4%

Fatigue 11% 7%

Decreased appetite 9% 4%

Headache 9% 8%

Pyrexia 6% 5%

Back pain 6% 4%

Dizziness 6% 4%

Hypertensionc 5% 2%


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SAFETY PROFILE (cont’d) SSc-ILD (cont'd)ADDITIONAL SAFETY DATA

• OFEV may increase the risk of bleeding. In SENSCIS®, bleeding events were reported in 11% of OFEV-treated patients vs 8% of placebo-treated patients1

• In the postmarketing period, nonserious and serious bleeding events, some of which were fatal, have been observed. Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk1

Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial infarction.1

b The category MACE comprised the following: any fatal event in system organ class cardiac disorders, any fatal event in system organ class vascular disorders, any fatal or nonfatal event in Standardized MedDRA Query “myocardial infarction (broad),” and “any fatal or nonfatal stroke.”5

c AE cardiac disorders include all adverse events that primarily affected the cardiac system (including, but not limited to: arrhythmia, atrial fibrillation, cardiac failure, and myocarditis).5

a Other reported bleeding events with OFEV compared to placebo, respectively, included lower gastrointestinal (GI) bleeding (2.8% vs 0.3%), oral GI bleeding (0.7% vs 0.3%), upper GI bleeding (0.3% vs 0.3%), central nervous system (CNS) bleeding (0.7% vs 0%), other bleeding (0.7% vs 0.7%), and hematopoietic thrombocytopenia (0.7% vs 0%).

Bleeding events observed in SENSCIS®5

Total bleeding eventsa

Epistaxis Contusion Rectal bleeding

Placebo(n=288), % (n)8.3% (24)3.8% (11)1.0% (3)0.0% (0)

OFEV® (nintedanib) capsules (n=288), % (n)11.1% (32)2.8% (8)2.4% (7)1.7% (5)

Arterial thromboembolic events

MACEb

MACE leading to death

Placebo(n=288), % (n)0.7% (2)

2.8% (8)0.7% (2)

OFEV(n=288), % (n)0.7% (2)

1.7% (5)0.3% (1)

AE cardiac disordersc

Serious AEFatal AE

MI MI leading to death

Placebo(n=288), % (n)9.0% (26)2.8% (8)0.7% (2)

0.7% (2)0.3% (1)

OFEV(n=288), % (n)8.7% (25)2.1% (6)0.3% (1)

0% (0)0% (0)

Cardiovascular AEs observed in SENSCIS®1,5

Cardiac AEs observed in SENSCIS®1,5


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SAFETY PROFILE (cont’d) SSc-ILD (cont'd)ADDITIONAL SAFETY DATA (cont’d)

• There was no difference between the OFEV and placebo groups in change from baseline in digital ulcer net burden at week 525

• In SENSCIS®, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, and GGT) and bilirubin1,3

• Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases1

• Cases of drug-induced liver injury (DILI) have been observed with OFEV treatment. In the clinical trials and postmarketing period, nonserious and serious cases of DILI were reported. Cases of severe liver injury with fatal outcome have been reported in the postmarketing period1

Liver enzyme and bilirubin elevations observed in SENSCIS®5

Digital ulcer adverse events observed in SENSCIS®5,7

Absolute change from baseline in digitalulcer net burden at Week 52, adjusted mean

Placebo(n=288), %0.06

OFEV® (nintedanib) capsules(n=288), %0.03

P value0.591

Maximum ALT ≥3 ULN ≥5 ULN ≥8 ULN

Maximum AST ≥3 ULN ≥5 ULN ≥8 ULN

Maximum AST and/or ALT ≥3 ULN ≥5 ULN ≥8 ULN

Maximum total bilirubin ≥1.5 ULN ≥2 ULN

Placebo(n=288), % (n)

0.7% (2)0.3% (1)0.3% (1)

0.3% (1)0.3% (1)0.3% (1)

0.7% (1)0.3% (1)0.3% (1)

0% (0)0% (0)

OFEV(n=288), % (n)

3.5% (10)1% (3)0% (0)

2.8% (8)0.7% (2)0% (0)

4.9% (14)1% (3)0% (0)

0.3% (1)0.3% (1)


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1. OFEV® (nintedanib) Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2019. 2. Crestani B, Huggins JT, Kaye M, et al. Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON. Lancet Respir Med. 2019;7(1):60-68. 3. Noth I, Oelberg D, Kaul M, Conoscenti CS, Raghu G. Safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis in the USA. Eur Respir J. 2018;52(1):1702106. 4. Richeldi L, du Bois RM, Raghu G, et al; for the INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082. 5. Data on file. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 6. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079-1087. 7. Distler O, Highland KB, Gahlemann AM, et al; SENSCIS Trial Investigators. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380(26):2518-2528.

REFERENCES


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USE IN SPECIFIC POPULATIONS

PREGNANCY1

Risk SummaryBased on findings from animal studies and its mechanism of action, OFEV® (nintedanib) capsules can cause fetal harm when administered to a pregnant woman. There are no data on the use of OFEV during pregnancy. In animal studies of pregnant rats and rabbits treated during organogenesis, nintedanib caused embryo-fetal deaths and structural abnormalities at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the US general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage in clinically recognized pregnancies is 15% to 20%.

DataAnimal DataIn animal reproduction toxicity studies, nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on a plasma AUC basis at maternal oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively).

Malformations included abnormalities in the vasculature, urogenital, and skeletal systems. Vasculature anomalies included missing or additional major blood vessels. Skeletal anomalies included abnormalities in the thoracic, lumbar, and caudal vertebrae (eg, hemivertebra, missing, or asymmetrically ossified), ribs (bifid or fused), and sternebrae (fused, split, or unilaterally ossified). In some fetuses, organs in the urogenital system were missing. In rabbits, a significant change in sex ratio was observed in fetuses (female:male ratio of approximately 71%:29%) at approximately 15 times the MRHD in adults (on an AUC basis at a maternal oral dose of 60 mg/kg/day). Nintedanib decreased postnatal viability of rat pups during the first 4 postnatal days when dams were exposed to less than the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

LACTATION1

Risk summaryThere is no information on the presence of nintedanib in human milk, the effects on the breast-fed infant, or the effects on milk production. Nintedanib and/or its metabolites are present in the milk of lactating rats.

Because of the potential for serious adverse reactions in nursing infants from OFEV® (nintedanib) capsules, advise women that breastfeeding is not recommended during treatment with OFEV.


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LACTATION1 (cont'd)DataMilk and plasma of lactating rats have similar concentrations of nintedanib and its metabolites.

FEMALES AND MALES OF REPRODUCTIVE POTENTIAL1

Based on findings from animal studies and its mechanism of action, OFEV® (nintedanib) capsules can cause fetal harm when administered to a pregnant woman and may reduce fertility in females of reproductive potential. Counsel patients on pregnancy prevention and planning.

Pregnancy testingVerify the pregnancy status of females of reproductive potential prior to treatment with OFEV and during treatment as appropriate.

ContraceptionOFEV can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV. Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 3 months after taking the last dose of OFEV. It is currently unknown whether nintedanib may reduce the effectiveness of hormonal contraceptives, therefore advise women using hormonal contraceptives to add a barrier method.

InfertilityBased on animal data, OFEV may reduce fertility in females of reproductive potential.

PEDIATRIC USE1

Safety and effectiveness in pediatric patients have not been established.

GERIATRIC USE1

Of the total number of subjects in phase 2 and 3 clinical studies of OFEV in IPF, 60.8% were 65 and over, while 16.3% were 75 and over. In SSc-ILD, 21.4% were 65 and older, while 1.9% were 75 and older. In phase 3 studies, no overall differences in effectiveness were observed between subjects who were 65 and over and younger subjects; no overall differences in safety were observed between subjects who were 65 and over or 75 and over and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

USE IN SPECIFIC POPULATIONS (cont'd)


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IMPO

RTA

NT

SAFE

TY

INFO

RMAT

ION

CLIN

ICA

L

PHA

RMA

COLO

GY

CLIN

ICA

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EFFI

CA

CY

SAFE

TY

PRO

FILE

PRO

DU

CT

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ESCR

IPTI

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HEPATIC IMPAIRMENT1

Nintedanib is predominantly eliminated via biliary/fecal excretion (greater than 90%). In a PK study performed in patients with hepatic impairment (Child Pugh A, Child Pugh B), exposure to nintedanib was increased. In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg twice daily. Monitor for adverse reactions and consider treatment interruption, or discontinuation for management of adverse reactions in these patients. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended.

RENAL IMPAIRMENT1

Based on a single-dose study, less than 1% of the total dose of nintedanib is excreted via the kidney. Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (less than 30 mL/min CrCl) and end-stage renal disease.

SMOKERS1

Smoking was associated with decreased exposure to OFEV, which may alter the efficacy profile of OFEV. Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using OFEV.

USE IN SPECIFIC POPULATIONS (cont'd)


49


USE

IN S

PEC

IFIC

PO

PULA

TIO

NS

EXEC

UTI

VE

SU

MM

ARY

IMPO

RTA

NT

SAFE

TY

INFO

RMAT

ION

CLIN

ICA

L

PHA

RMA

COLO

GY

CLIN

ICA

L

EFFI

CA

CY

SAFE

TY

PRO

FILE

PRO

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CT

D

ESCR

IPTI

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1. OFEV® (nintedanib) Prescribing Information. Ridgefield, CT: Boehringer Ingelheim; 2019.

REFERENCE


Copyright © 2019 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (09/19) PC-US-110856



https://www.boehringer-ingelheim.us

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