Ofev

Nintedanib esilate.

Each capsule contains 100 mg or 150 mg of nintedanib (= free base) corresponding to 120.4 mg or 180.6 mg 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) (= nintedanib esilate).
Nintedanib esilate (Ofev) capsules, 100 mg are peach-coloured, opaque, oblong, soft gelatin capsules, imprinted in black on one side with the Boehringer Ingelheim company symbol and with "100". The capsule contains a bright yellow viscous suspension.
Nintedanib esilate (Ofev) capsules, 150 mg are brown-coloured, opaque, oblong, soft gelatin capsules, imprinted in black on one side with the Boehringer Ingelheim company symbol and with "150". The capsule contains a bright yellow viscous suspension.
Excipients/Inactive Ingredients: Capsule fill: Medium chain triglycerides, hard fat, soya lecithin (E322).
Capsule shell: Gelatin, glycerol 85%, titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172), black ink (Opacode).
Black ink: Shellac glaze, iron oxide black (E172), propylene glycol (E1520).

Pharmacotherapeutic group: Antineoplastic agents - Protein kinase inhibitors. ATC code: L01EX09.
Pharmacology: Mode of Action: Oncology: Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and β) and fibroblast growth factor receptors (FGFR 1-3) kinase activity. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling which is crucial for the proliferation and survival of endothelial as well as perivascular cells (pericytes and vascular smooth muscle cells). In addition Fms-like tyrosine-protein kinase (Flt)-3, lymphocyte-specific tyrosine-protein kinase (Lck) and proto-oncogene tyrosine-protein kinase Src (Src) are inhibited.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Nintedanib is a small molecule tyrosine kinase inhibitor including the receptors platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, and vascular endothelial growth factor receptor (VEGFR) 1-3. In addition, nintedanib inhibits Lck, Lyn, Src, and CSF1R kinases. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these kinases and blocks the intracellular signalling cascades, which have been demonstrated to be involved in the pathogenesis of fibrotic tissue remodelling in interstitial lung diseases.
Pharmacodynamics: Oncology: Tumour angiogenesis is an essential feature contributing to tumour growth, progression and metastasis formation and is predominantly triggered by the release of pro-angiogenic factors secreted by the tumour cell (i.e. VEGF and bFGF) to attract host endothelial as well as perivascular cells to facilitate oxygen and nutrient supply through the host vascular system. In preclinical disease models nintedanib, as single agent, effectively interfered with the formation and maintenance of the tumour vascular system resulting in tumour growth inhibition and tumour stasis. In particular, treatment of tumour xenografts with nintedanib led to a rapid reduction in tumour micro vessel density, pericytes vessel coverage and tumour perfusion.
Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) measurements showed an anti-angiogenic effect of nintedanib in humans. It was not clearly dose dependent, but most responses were seen at doses of ≥ 200 mg. Logistic regression revealed a statistically significant association of the anti-angiogenic effect to nintedanib exposure. DCE-MRI effects were seen 24-48 h after the first intake of the medicinal product and were preserved or even increased after continuous treatment over several weeks. No correlation of the DCE-MRI response and subsequent clinically significant reduction in target lesion size was found, but DCE-MRI response was associated with disease stabilization.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): In in vitro studies using human cells nintedanib has been shown to inhibit processes assumed to be involved in the initiation of the fibrotic pathogenesis, the release of pro-fibrotic mediators from peripheral blood monocytic cells and macrophage polarisation to alternatively activated macrophages. Nintedanib has been demonstrated to inhibit fundamental processes in organ fibrosis, proliferation and migration of fibroblasts and transformation to the active myofibroblast phenotype and secretion of extracellular matrix. In animal studies in multiple models of IPF, SSc/SSc-ILD, RA-ILD and other organ fibrosis, nintedanib has shown anti-inflammatory effects and anti-fibrotic effects in the lung, skin, heart, kidney, and liver. Nintedanib also exerted vascular activity. It reduced dermal microvascular endothelial cell apoptosis and attenuated pulmonary vascular remodelling by reducing the proliferation of vascular smooth muscle cells, the thickness of pulmonary vessel walls, and percentage of occluded pulmonary vessels.
Clinical trials: Oncology: Efficacy in the pivotal phase III trial LUME-Lung 1: The efficacy and safety of Nintedanib esilate (Ofev) was investigated in 1314 patients with locally advanced, metastatic or recurrent NSCLC after one prior line of chemotherapy. The trial included 658 patients (50.1%) with adenocarcinoma, 555 patients (42.2%) with squamous cell carcinoma, and 101 patients (7.7%) with other tumour histologies.
Patients were randomized (1:1) to receive Nintedanib esilate (Ofev) 200 mg orally twice daily in combination with 75 mg/m² of i.v. docetaxel every 21 days (n=655) or placebo orally twice daily in combination with 75 mg/m² of docetaxel every 21 days (n=659). Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) status (0 vs. 1), bevacizumab pretreatment (yes vs. no), brain metastasis (yes vs. no) and tumour histology (squamous vs. non-squamous tumour histology). Patient characteristics were balanced between treatment arms within the overall population and within the adenocarcinoma patients. In the overall population 72.7% of the patients were male. The majority of patients were non-Asian (81.6%), the median age was 60.0 years, the baseline ECOG performance status was 0 (28.6%) or 1 (71.3%); one patient had a baseline ECOG performance status of 2. 5.8% of the patients had stable brain metastasis at study entry and 3.8% had prior bevacizumab treatment. The disease stage was determined at the time of diagnosis using Union Internationale Contre le Cancer (UICC)/American Joint Committee on Cancer (AJCC) Edition 6 or Edition 7. In the overall population, 16.0% of the patients had disease stage <IIIB/IV, 22.4%, had disease stage IIIB and 61.6% had disease stage IV. 9.2% of the patients entered the study with locally recurrent disease stage as had been evaluated at baseline. For patients with tumour of adenocarcinoma histology, 15.8% had disease stage <IIIB/IV, 15.2%, had disease stage IIIB and 69.0% had disease stage IV. 5.8% of the adenocarcinoma patients entered the study with locally recurrent disease stage as had been evaluated at baseline. 'Locally recurrent' was defined as local re-occurrence of the tumour without metastases at study entry.
The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee (IRC) based on the intent-to-treat (ITT) population and tested by histology. Overall survival (OS) was the key secondary endpoint. Other efficacy outcomes included objective response, disease control, change in tumour size and health-related quality of life.
As shown in Table 1, the addition of Nintedanib esilate (Ofev) to docetaxel led to a statistically significant reduction in the risk of progression or death by 21% for the overall population (HR 0.79; 95% CI: 0.68 - 0.92; p=0.0019) as determined by the IRC. This result was confirmed in the follow-up PFS analysis (HR 0.85, 95% CI: 0.75-0.96; p=0.0070) which included all events collected at the time of the final OS analysis. Overall survival analysis in the overall population did not reach statistical significance (HR 0.94; 95% CI: 0.83-1.05).
Of note, pre-planned analyses according to histology showed statistically significant difference in OS between treatment arms in the adenocarcinoma population only.
The addition of Nintedanib esilate (Ofev) to docetaxel led to a statistically significant reduction in the risk of progression or death by 23% for the adenocarcinoma population (HR 0.77; 95% CI: 0.62-0.96). In line with these observations, related study endpoints such as disease control and change in tumour size showed significant improvements. (See Table 1.)

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A statistically significant improvement in OS favouring treatment with Nintedanib esilate (Ofev) plus docetaxel was demonstrated in patients with adenocarcinoma with a 17% reduction in the risk of death (HR 0.83, p=0.0359) and a median OS improvement of 2.3 months (10.3 vs. 12.6 months, Figure 1). (See Figure 1.)

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A pre specified evaluation was performed in the population of adenocarcinoma patients considered to have entered the study with a particularly poor treatment prognosis, namely, patients who progressed during or shortly after 1^st line therapy prior to study entry. This population included those adenocarcinoma patients identified at baseline as having progressed and entered the study less than 9 months since start of their first-line therapy. Treatment of these patients with Nintedanib esilate (Ofev) in combination with docetaxel reduced the risk of death by 25%, compared with placebo plus docetaxel (HR 0.75; 95% CI: 0.60 - 0.92; p=0.0073). Median OS improved by 3 months (Nintedanib esilate (Ofev): 10.9 months; placebo: 7.9 months).
In a post-hoc analysis in adenocarcinoma patients having progressed and entered the study ≥9 months since start of their first-line therapy the difference did not reach statistical significance (HR for OS: 0.89, 95% CI 0.66-1.19).
The proportion of adenocarcinoma patients with stage <IIIB/IV at diagnosis was small and balanced across treatment arms (placebo: 54 patients (16.1%); Nintedanib esilate (Ofev): 50 patients, (15.5%)). The HR for these patients for PFS and OS was 1.24 (95% CI: 0.68, 2.28) and 1.09 (95% CI: 0.70, 1.70), respectively. However, the sample size was small, there was no significant interaction and the CI was wide and included the HR for OS of the overall adenocarcinoma population.
Idiopathic Pulmonary Fibrosis, other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): The clinical efficacy of Nintedanib esilate (Ofev) has been studied in patients with IPF in two phase III, randomised, double-blind, placebo-controlled studies with identical design (INPULSIS-1 and INPULSIS-2). Patients were randomized in a 3:2 ratio to treatment with Nintedanib esilate (Ofev) 150 mg or placebo twice daily for 52 weeks.
The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC). The key secondary endpoints were changed from baseline in Saint George's Respiratory Questionnaire (SGRQ) total score at 52 weeks and time to first acute IPF exacerbation.
Annual rate of decline in FVC: The annual rate of decline of FVC (in mL) was significantly reduced in patients receiving Nintedanib esilate (Ofev) compared to patients receiving placebo. The treatment effect was consistent in both trials. See Table 2 for individual and pooled study results. (See Table 2.)

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The robustness of the effect of Nintedanib esilate (Ofev) in reducing the annual rate of decline in FVC was confirmed in all pre-specified sensitivity analyses.
In addition, similar effects were observed on other lung function endpoints e.g. change from baseline in FVC at week 52 and FVC responder analyses providing further substantiation of the effects of Nintedanib esilate (Ofev) on slowing disease progression. See Figure 2 for the evolution of change from baseline over time in both treatment groups, based on the pooled analysis of studies. INPULSIS-1 and INPULSIS-2. (See Figure 2.)

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FVC responder analysis: In both INPULSIS trials, the proportion of FVC responders, defined as patients with an absolute decline in FVC% predicted no greater than 5% (a threshold indicative of the increasing risk of mortality in IPF), was significantly higher in the Nintedanib esilate (Ofev) group as compared to placebo. Similar results were observed in analyses using a conservative threshold of 10%. See Table 3 for individual and pooled study results. (See Table 3.)

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Time to progression (≥10% absolute decline of FVC % predicted or death): In both INPULSIS trials, the risk of progression was statistically significantly reduced for patients treated with Nintedanib esilate (Ofev) compared with placebo. In the pooled analysis, the HR was 0.60 indicating a 40% reduction in the risk of progression for patients treated with Nintedanib esilate (Ofev) compared with placebo, see Table 4. (See Table 4.)

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Change from baseline in SGRQ total score at week 52: St. George's Respiratory Questionnaire (SGRQ) total score measuring health related quality of life (HRQoL) was analysed at 52 weeks. In INPULSIS-2, patients receiving placebo had a larger increase from baseline SGRQ total score as compared to patients receiving Nintedanib esilate (Ofev) 150 mg bid. The deterioration of HRQoL was smaller in the Nintedanib esilate (Ofev) group; the difference between the treatment groups was statistically significant (-2.69; 95% CI: -4.95, -0.43; p=0.0197).
In INPULSIS-1, the increase from baseline in SGRQ total score at week 52 was comparable between Nintedanib esilate (Ofev) and placebo (difference between treatment groups: -0.05; 95% CI: -2.50, 2.40; p=0.9657). In the pooled analysis of the INPULSIS trials, the estimated mean change from baseline to week 52 in SGRQ total score was smaller in the nintedanib group (3.53) than in the placebo group (4.96), with a difference between the treatment groups of -1.43 (95% CI: -3.09, 0.23; p=0.0923). Overall, the effect of Nintedanib esilate (Ofev) on health-related quality of life as measured by the SGRQ total score is modest, indicating less worsening compared to placebo.
Time to first acute IPF exacerbation: In the INPULSIS-2 trial, the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving Nintedanib esilate (Ofev) compared to placebo, in the INPULSIS-1 trial there was no difference between the treatment groups. In the pooled analysis of the INPULSIS trials, a numerically lower risk of first acute exacerbation was observed in patients receiving Nintedanib esilate (Ofev) compared to placebo. See Table 5 for individual and pooled study results. (See Table 5.)

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All adverse events of acute IPF exacerbation reported by the investigator were adjudicated by a blinded adjudication committee. A pre-specified sensitivity analysis of the time to first 'confirmed' or 'suspected' adjudicated acute IPF exacerbation was performed on the pooled data. The frequency of patients with at least 1 adjudicated exacerbation occurring within 52 weeks was lower in the Nintedanib esilate (Ofev) group (1.9% of patients) than in the placebo group (5.7% of patients). Time to event analysis of the adjudicated exacerbation events using pooled data yielded an HR of 0.32 (95% CI 0.16, 0.65; p=0.0010). This indicates that the risk of having a first acute IPF exacerbation was statistically significantly lower in the Nintedanib esilate (Ofev) group than in the placebo group at any time point.
Survival analysis: In the pre-specified pooled analysis of survival data of the INPULSIS trials, overall mortality over 52 weeks was lower in the Nintedanib esilate (Ofev) group (5.5%) compared with the placebo group (7.8%). The analysis of time to death resulted in a HR of 0.70 (95% CI 0.43, 1.12; p=0.1399). The results of all survival endpoints (such as on-treatment mortality and respiratory mortality) showed a consistent numerical difference in favour of Nintedanib esilate (Ofev) (See Table 6).

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Supportive evidence from the phase II trial (1199.30) Nintedanib esilate (Ofev) 150 mg twice daily results: Additional evidence of efficacy is provided by the randomised, double-blind, placebo-controlled, dose finding phase II trial including a Nintedanib esilate (Ofev) 150 mg bid dose group.
The primary endpoint, rate of decline in FVC over 52 weeks was lower in the Nintedanib esilate (Ofev) arm (-0.060 L/year, N=84) than the placebo arm (-0.190 L/year, N=83). The estimated difference between the treatment groups was 0.131 L/year (95% CI 0.027, 0.235). The difference between the treatment groups reached nominal statistical significance (p=0.0136).
The estimated mean change from baseline in SGRQ total score at 52 weeks was 5.46 for placebo, indicating worsening of the health-related quality of life and -0.66 for Nintedanib esilate (Ofev), indicating stable health-related quality of life. The estimated mean difference for Nintedanib esilate (Ofev) compared with placebo was -6.12 (95% CI: -10.57, -1.67; p=0.0071).
The number of patients with acute IPF exacerbations over 52 weeks was lower in the Nintedanib esilate (Ofev) group (2.3%, N=86) compared to placebo (13.8%, N=87). The estimated hazard ratio of nintedanib versus placebo was 0.16 (95% CI 0.04, 0.71; p=0.0054).
Long-term treatment with Nintedanib esilate (Ofev) in patients with IPF (INPULSIS-ON): An open-label extension trial of Nintedanib esilate (Ofev) included 734 patients with IPF. Some patients were treated with Nintedanib esilate (Ofev) for more than 5 years. Patients who completed the 52-week treatment period in an INPULSIS trial received open-label Nintedanib esilate (Ofev) treatment in the extension trial INPULSIS-ON. Median exposure time for patients treated with Nintedanib esilate (Ofev) in both the INPULSIS and INPULSIS-ON trials was 44.7 months (range 11.9-68.3). The adjusted annual rate of decline in FVC over 192 weeks was -135.1 (5.8) mL/year in all patients treated and were consistent with the annual rate of FVC decline in patients treated with Nintedanib esilate (Ofev) in the INPULSIS phase III trials (-113.6 mL per year). The adverse event profile of Nintedanib esilate (Ofev) in INPULSIS-ON was similar to that in the INPULSIS phase III trials.
IPF patients with advanced lung function impairment (INSTAGE): A double-blind, randomised, parallel-group trial evaluated the efficacy and safety of Nintedanib esilate (Ofev) co-administered with oral sildenafil, compared to treatment with Nintedanib esilate (Ofev) alone in 273 patients with IPF and advanced lung function impairment (DLCO <35% predicted) for 24 weeks. The decline in FVC in patients treated with Nintedanib esilate (Ofev) alone was consistent with the decline in FVC in patients with less advanced disease and treated with Nintedanib esilate (Ofev) in the INPULSIS phase III trials. The addition of sildenafil to Nintedanib esilate (Ofev) did not provide significant benefit in terms of quality of life vs Nintedanib esilate (Ofev) alone. The safety and tolerability profile of Nintedanib esilate (Ofev) in IPF patients with advanced lung function impairment was consistent with that seen in the INPULSIS phase III trials. The adverse event profile of the combination of Nintedanib esilate (Ofev) and sildenafil was in line with the established safety profile of each component, with no increase in serious or fatal adverse events compared with Nintedanib esilate (Ofev) alone.
Additional data from the phase IV INJOURNEY trial with Nintedanib esilate (Ofev) 150 mg twice daily and add-on pirfenidone: Concomitant treatment with Nintedanib esilate (Ofev) and pirfenidone has been investigated in an exploratory open-label, randomised trial of Nintedanib esilate (Ofev) 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times a day) compared to Nintedanib esilate (Ofev) 150 mg twice daily alone in 105 randomised patients for 12 weeks. The primary endpoint was the percentage of patients with gastrointestinal adverse events from baseline to week 12. Gastrointestinal adverse events were frequent and in line with the established safety profile of each component. Diarrhoea, nausea and vomiting were the most frequent adverse events reported in 20 (37.7%) versus 16 (31.4%), in 22 (41.5%) versus 6 (11.8%) and in 15 (28.3%) versus 6 (11.8%) patients, treated with pirfenidone added to Nintedanib esilate (Ofev) versus nintedanib alone, respectively.
Mean (SE) absolute changes from baseline in FVC at week 12 were -13.3 (17.4) mL in patients treated with nintedanib with add-on pirfenidone (n=48) compared to -40.9 (31.4) mL in patients treated with nintedanib alone (n=44).
Other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype: The clinical efficacy of Nintedanib esilate (Ofev) has been studied in patients with chronic fibrosing ILDs with a progressive phenotype in a double-blind, randomised, placebo-controlled phase III trial (INBUILD). Patients with IPF were excluded. Patients with a clinical diagnosis of chronic fibrosing ILD were selected if they had relevant fibrosis (>10% fibrotic features) on high resolution computed tomography (HRCT) and presented with clinical signs of progression. A total of 663 patients were randomised in a 1:1 ratio to receive either Nintedanib esilate (Ofev) 150 mg bid or matching placebo for at least 52-weeks (The median Nintedanib esilate (Ofev) exposure over the whole trial was 17.4 months and the mean Nintedanib esilate (Ofev) exposure over the whole trial was 15.6 months). Randomisation was stratified based on HRCT fibrotic pattern as assessed by central readers. 412 patients with HRCT with usual interstitial pneumonia (UIP)-like fibrotic pattern and 251 patients with other HRCT fibrotic patterns were randomised. There were 2 co-primary populations defined for the analyses in this trial: all patients (the overall population) and patients with HRCT with UIP-like fibrotic pattern. Patients with other HRCT fibrotic patterns represented the 'complementary' population.
The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC) (in mL) over 52 weeks. Main secondary endpoints were absolute change from baseline in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score at week 52, time to first acute ILD exacerbation or death over 52 weeks, and time to death over 52 weeks.
Patients had a mean (standard deviation [SD, Min-Max])) age of 65.8 (9.8, 27-87) years and a mean FVC percent predicted of 69.0% (15.6, 42-137). The underlying clinical ILD diagnoses in groups represented in the trial were hypersensitivity pneumonitis (26.1%), autoimmune ILDs (25.6%), idiopathic nonspecific interstitial pneumonia (18.9%), unclassifiable idiopathic interstitial pneumonia (17.2%), and other ILDs (12.2%).
Annual rate of decline in FVC: The annual rate of decline in FVC (in mL) over 52 weeks was significantly reduced by 107.0 mL: in patients receiving Nintedanib esilate (Ofev) compared to patients receiving placebo (Table 7) corresponding to a relative treatment effect of 57.0%. (See Table 7.)

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Similar results were observed in the co-primary population of patients with HRCT with UIP-like fibrotic pattern: the annual rate of decline in FVC was -211.1 mL/year in the placebo group (n=206) and -82.9 mL/year in the Nintedanib esilate (Ofev) group (n=206). The difference between the treatment groups was 128.2 mL/year (95% CI: 70.8, 185.6; p<0.0001). Further, the treatment effect was consistent in the complementary population of patients with other HRCT fibrotic patterns. The annual rate of decline in FVC was -154.2 mL/year in the placebo group (n=125) and -79.0 mL/year in the Nintedanib esilate (Ofev) group (n=126). The difference between the treatment groups was 75.2 mL/year (95% CI: 15.5, 135.0) with a nominal p-value <0.05 (p=0.014). (See Figure 3.)

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The robustness of the effect of Nintedanib esilate (Ofev) in reducing the annual rate of decline in FVC was confirmed in all pre-specified sensitivity analyses and consistent results were observed in all pre-specified subgroups (e.g. gender, age group, race, baseline FVC% predicted, and original underlying clinical ILD diagnosis in groups).
Figure 4 shows the evolution of change in FVC from baseline over time in the treatment groups. (See Figure 4.)

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In addition, favourable effects of Nintedanib esilate (Ofev) were observed on the adjusted mean absolute change form baseline in FVC% predicted at week 52. The adjusted mean absolute change from baseline to week 52 in FVC% predicted was lower in the nintedanib group (-2.62%) than in the placebo group (-5.86%). The adjusted mean difference between the treatment groups was 3.24 (95% CI: 2.09, 4.40, nominal p<0.0001).
FVC responder analysis: The proportion of FVC responders, defined as patients with a relative in FVC% predicted no greater than 5%, was higher in the Nintedanib esilate (Ofev) group as compared to placebo. Similar results were observed in analyses using a threshold of 10% (Table 8). (See Table 8.)

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Time to first acute ILD exacerbation or death: The proportion of patients with at least one event of first acute ILD exacerbation or death over 52 weeks was 7.8% in the Nintedanib esilate (Ofev) group and 9.7% in the placebo group. The risk of having an event of first acute ILD exacerbation or death was numerically lower in the Nintedanib esilate (Ofev) group compared to placebo: HR 0.80 (95% CI: 0.48, 1.34; nominal p=0.3948).
When analysing data over the whole trial, the risk of first acute ILD exacerbation or death further decreased in the Nintedanib esilate (Ofev) group compared with the placebo group: the HR was 0.67 (95% CI: 0.46, 0.98; nominal p=0.0387), indicating a 33% reduction in the risk of first acute ILD exacerbation or death in patients receiving Nintedanib esilate (Ofev) compared to placebo (Figure 5). (See Figure 5.)

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Survival analysis: The proportion of patients who died over 52 weeks was 4.8% in the Nintedanib esilate (Ofev) group compared to 5.1% in the placebo group. The HR was 0.94 (95% CI: 0.47, 1.86; nominal p=0.8544).
In the analysis of data over the whole trial, the risk of death was lower in the Nintedanib esilate (Ofev) group compared to the placebo group. The HR was 0.78 (95% CI: 0.50, 1.21; nominal p=0.2594), indicating a 22% reduction in the risk of death in patients receiving Nintedanib esilate (Ofev) compared to placebo.
Time to progression (≥10% absolute decline of FVC% predicted) or death: In the INBUILD trial, the risk of progression (≥10% absolute decline of FVC% predicted) or death was reduced for patients treated with Nintedanib esilate (Ofev). The proportion of patients with an event over 52 weeks was 25.6% in the Nintedanib esilate (Ofev) group and 37.5% in the placebo group. The HR was 0.65 (95% CI: 0.49, 0.85; nominal p=0.0017).
In the analysis of data over the whole trial, the proportion of patients with an event of progression (≥10% absolute decline of FVC% predicted) or death was 40.4% in the Nintedanib esilate (Ofev) group and 54.7% in the placebo group. The HR was 0.66 (95% CI: 0.53, 0.83; p=0.0003), indicating a 34% reduction of the risk of progression (≥10% absolute decline of FVC% predicted) or death in patients receiving Nintedanib esilate (Ofev) compared to placebo.
Quality of life: In the INBUILD trial health related quality of life at 52 weeks was measured using the: Absolute change from baseline in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score (range from 0-100, higher scores indicate a better health status); Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms dyspnoea domain score (range from 0-100, the higher the score the greater the impairment); Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms cough domain score (range from 0-100, the higher the score the greater the impairment).
The adjusted mean change from baseline in K-BILD total score at week 52 was -0.79 units in the placebo group and 0.55 in the Nintedanib esilate (Ofev) group. The difference between the treatment groups was 1.34 (95% CI: -0.31, 2.98; nominal p=0.1115).
The adjusted mean absolute change from baseline in L-PF Symptoms dyspnoea domain score at week 52 was 4.28 in the Nintedanib esilate (Ofev) group compared with 7.81 in the placebo group.
The adjusted mean difference between the groups in favour of Nintedanib esilate (Ofev) was -3.53 (95% CI: -6.14, -0.92; nominal p=0.0081). The adjusted mean absolute change from baseline in L-PF Symptoms cough domain score at week 52 was -1.84 in the Nintedanib esilate (Ofev) group compared with 4.25 in the placebo group. The adjusted mean difference between the groups in favour of Nintedanib esilate (Ofev) was -6.09 (95% CI: -9.65, -2.53; nominal p=0.0008).
Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): The clinical efficacy of Nintedanib esilate (Ofev) has been studied in patients with SSc-ILD in a double-blind, randomized, placebo-controlled phase III trial (SENSCIS). Patients were diagnosed with SSc-ILD based upon the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc and a chest high resolution computed tomography (HRCT) scan conducted within the previous 12 months. A total of 580 patients were randomized in a 1:1 ratio to receive either Nintedanib esilate (Ofev) 150 mg bid or matching placebo for at least 52 weeks, of which 576 patients were treated. Randomisation was stratified by Antitopoisomerase Antibody status (ATA). Individual patients stayed on blinded trial treatment for up to 100 weeks (median Nintedanib esilate (Ofev) exposure 15.4 months; mean Nintedanib esilate (Ofev) exposure 14.5 months.
The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC) over 52 weeks. Key secondary endpoints were absolute change from baseline in the modified Rodnan Skin Score (mRSS) at week 52 and absolute change from baseline in the Saint George's Respiratory Questionnaire (SGRQ) total score at week 52.
In the overall population, 75.2% of the patients were female. The mean (standard deviation [SD, Min-Max]) age was 54.0 (12.2. 20-79) years. Overall, 51.9% of patients had diffuse cutaneous Systemic Sclerosis (SSc) and 48.1% had limited cutaneous SSc. The mean (SD) time since first onset of a non-Raynaud symptom was 3.49 (1.7) years. 49.0% of patients were on stable therapy with mycophenolate at baseline (46.5% mycophenolate mofetil, 1.9% mycophenolate sodium, 0.5% mycophenolic acid). The safety profile in patients with or without mycophenolate at baseline was comparable.
Annual rate of decline in FVC: The annual rate of decline of FVC (in mL) over 52 weeks was significantly reduced by 41.0 mL in patients receiving Nintedanib esilate (Ofev) compared to patients receiving placebo (Table 9) corresponding to a relative treatment effect of 43.8%. (See Table 9.)

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The effect of Nintedanib esilate (Ofev) in reducing the annual rate of decline in FVC was similar across pre-specified sensitivity analyses and no heterogeneity was detected in pre-specified subgroups (e.g. by age, gender, and mycophenolate use).
In addition, similar effects were observed on other lung function endpoints, e.g. absolute change from baseline FVC in mL at week 52 (Figure 6 and Table 10) and rate of decline in FVC in % predicted over 52 weeks (Table 11) providing further substantiation of the effects of Nintedanib esilate (Ofev) on slowing progression of SSc-ILD. Furthermore, fewer patients in the Nintedanib esilate (Ofev) group had an absolute FVC decline >5% predicted (20.6% in the Nintedanib esilate (Ofev) group vs 28.5% in the placebo group, OR=0.65, p=0.0287). The relative FVC decline in mL >10% was comparable between both groups (16.7% in the Nintedanib esilate (Ofev) group vs 18.1% in the placebo group, OR=0.91, p=0.6842). In these analyses, missing FVC values at week 52 were imputed with the patient's worst value on treatment.
An exploratory analysis of data up to 100 weeks (maximum treatment duration in SENSCIS) suggested that the on treatment effect of Nintedanib esilate (Ofev) on slowing progression of SSc-ILD persisted beyond 52 weeks. (See Figure 6, Tables 10 and 11.)

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Change from baseline in Modified Rodnan Skin Score (mRSS) at week 52: The adjusted mean absolute change from baseline in mRSS at week 52 was comparable between the Nintedanib esilate (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; p=0.5785).
Change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score at week 52: The adjusted mean absolute change from baseline in SGRQ total score at week 52 was comparable between the Nintedanib esilate (Ofev) group (0.81 (95% CI -0.92, 2.55)) and the placebo group (-0.88 (95% CI -2.58, 0.82)). The adjusted mean difference between the treatment groups was 1.69 (95% CI -0.73, 4.12; p=0.1711).
Survival analysis: Mortality over the whole trial was comparable between the Nintedanib esilate (Ofev) group (N=10; 3.5%) and the placebo group (N=9; 3.1%). The analysis of time to death over the whole trial resulted in a HR of 1.16 (95% CI 0.47, 2.84; p=0.7535).
Quality of Life: Oncology: Treatment with Nintedanib esilate (Ofev) did not significantly change the time to deterioration of the pre-specified symptoms cough, dyspnoea and pain, but resulted in a significant deterioration in the diarrhoea symptom scale. Nevertheless, the overall treatment benefit of nintedanib was observed without adversely affecting self-reported quality of life.
Effect on QT interval: QT/QTc measurements were recorded and analysed from a dedicated study comparing nintedanib monotherapy against sunitinib monotherapy in patients with renal cell carcinoma. In this study single oral doses 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.
Oncology: However, no thorough QT-trial of nintedanib administered in combination with docetaxel was conducted.
Paediatric population: Oncology: No clinical trials have been conducted with nintedanib in children and adolescents for the oncology indication.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Treatment of paediatric patients with nintedanib for fibrosing Interstitial Lung Diseases (ILDs) is not registered.
Pharmacokinetics: The pharmacokinetics (PK) of nintedanib can be considered linear with respect to time (i.e. single-dose data can be extrapolated to multiple-dose data). Accumulation upon multiple administrations was 1.04-fold for C_max and 1.38-fold for AUC_τ. Nintedanib trough concentrations remained stable for more than one year.
Absorption: Nintedanib reached maximum plasma concentrations approximately 2-4 hours after oral administration as soft gelatin capsule under fed conditions (range 0.5-8 hours). The absolute bioavailability of a 100 mg dose was 4.69% (90% CI: 3.615-6.078) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.
Nintedanib exposure increased dose-proportionally in the dose range of 50-450 mg once daily and 150-300 mg twice daily. Steady state plasma concentrations were achieved within one week of dosing at the latest.
After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (CI: 95.3-152.5%) and absorption was delayed (median t_max fasted: 2.00 h; fed: 3.98 hours).
In an in vitro study, mixing nintedanib capsules with a small amount of apple sauce or chocolate pudding for up to 15 minutes did not have any impact on the pharmaceutical quality. Therefore, taking the capsules with soft food would not be expected to alter the clinical effect when taken immediately.
Distribution: Nintedanib follows at least bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution (V_ss: 1050 L, 45.0 % gCV) 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 0.869.
Biotransformation: The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by 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 CYP pathways, with CYP 3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human ADME study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.
Oncology: In preclinical in vivo experiments, BIBF 1202 did not show efficacy despite its activity at target receptors of the substance.
Elimination: Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min, 28.8% gCV). Urinary excretion of the unchanged active substance within 48 hours was about 0.05% of dose (31.5% gCV) after oral and about 1.4% of the dose (24.2% gCV) after intravenous administration; the renal clearance was 20 mL/min (32.6% gCV). The major route of elimination of drug related radioactivity after oral administration of [¹⁴C] nintedanib was via faecal/biliary excretion (93.4% of dose, 2.61% gCV). The contribution of renal excretion to the total clearance was low (0.649% of dose, 26.3% gCV). The overall recovery was considered complete (above 90%) within 4 days after dosing. The terminal half-life of nintedanib was between 10 and 15 h (gCV % approximately 50%).
Exposure-response relationship: Oncology: In exploratory pharmacokinetic (PK)-adverse event analyses, higher exposure to nintedanib tended to be associated with liver enzyme elevations, but not with gastrointestinal adverse events.
PK-efficacy analyses were not performed for clinical endpoints. Logistic regression revealed a statistically significant association between nintedanib exposure and DCE-MRI response.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Exposure-response analyses of patients with IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD indicated an E_max-like relationship between exposure and the annual rate of decline in FVC with an EC₅₀ of around 3 ng/mL (relative standard errors: 55-67%). For comparison, median observed nintedanib trough concentrations for 150 mg bid Nintedanib esilate (Ofev) were about 10 ng/mL. With respect to safety, there seemed to be a weak relationship between nintedanib plasma exposure and ALT and/or AST elevations. Actual administered dose might be the better predictor for the risk of developing diarrhea of any intensity, even if plasma exposure as risk determining factor could not be ruled out (see Precautions).
Intrinsic and Extrinsic Factors; Special Populations: The PK properties of nintedanib were similar in healthy volunteers, patients with IPF, patients with other chronic fibrosing ILDs with a progressive phenotype, patients with SSc-ILD, and cancer patients. Based on results of Population PK (PopPK) analyses and descriptive investigations, exposure to nintedanib was not influenced by sex (body weight corrected), mild and moderate renal impairment (estimated by creatinine clearance), liver metastases, ECOG performance score, alcohol consumption, or P-gp genotype. Population PK analyses indicated moderate effects on exposure to nintedanib depending on age, body weight, and race (see as follows). Based on the high interindividual variability of exposure observed in the clinical trials these effects are not considered clinically relevant (see Precautions).
Age: Exposure to nintedanib increased linearly with age. AUC_τ,ss decreased by 16% for a 45-year old patient (5^th percentile) and increased by 13% for a 76-year old patient (95^th percentile) relative to a patient with the median age of 62 years. The age range covered by the analysis was 29 to 85 years; approximately 5% of the population was older than 75 years.
Body weight: An inverse correlation between body weight and exposure to nintedanib was observed. AUC_τ,ss increased by 25% for a 50 kg patient (5^th percentile) and decreased by 19% for a 100 kg patient (95^th percentile) relative to a patient with the median weight of 71.5 kg.
Race: The population mean exposure to nintedanib was 33-50% higher in Chinese, Taiwanese, and Indian patients and 16% higher in Japanese patients while it was 16-22% lower in Koreans compared to Caucasians (body weight corrected).
Data from black individuals was very limited but in the same range as for Caucasians.
Hepatic impairment: In a dedicated single dose phase I study and compared to healthy subjects, exposure to nintedanib based on C_max and AUC was 2.2-fold higher in volunteers with mild hepatic impairment (Child Pugh A; 90% CI 1.3-3.7 for C_max and 1.2-3.8 for AUC, respectively). In volunteers with moderate hepatic impairment (Child Pugh B), exposure was 7.6-fold higher based on C_max (90% CI 4.4-13.2) and 8.7-fold higher (90% CI 5.7-13.1) based on AUC, respectively, compared to healthy volunteers. Subjects with severe hepatic impairment (Child Pugh C) have not been studied.
Concomitant treatment with pirfenidone: Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): In a dedicated pharmacokinetic study, concomitant treatment of Nintedanib esilate (Ofev) with pirfenidone was investigated in patients with IPF. Group 1 received a single dose of 150 mg Nintedanib esilate (Ofev) before and after uptitration to 801 mg pirfenidone three times a day at steady state. Group 2 received steady state treatment of 801 mg pirfenidone three times a day and had a PK profiling before and after at least 7 days of co-treatment with 150 mg Nintedanib esilate (Ofev) twice daily. In group 1, the adjusted geometric mean ratios (90% confidence interval (CI)) were 93% (57%-151%) and 96% (70%-131%) for C_max and AUC_0-tz of nintedanib, respectively (n=12). In group 2, the adjusted geometric mean ratios (90% CI)) were 97% (86%-110%) and 95% (86%-106%) for C_max,ss and AUC_τ,ss of pirfenidone, respectively (n=12).
Based on these results, there is no evidence of a relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when administered in combination.
Concomitant treatment with bosentan: Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): In a dedicated pharmacokinetic study, concomitant treatment of Nintedanib esilate (Ofev) with bosentan was investigated in healthy volunteers. Subjects received a single dose of 150 mg Nintedanib esilate (Ofev) before and after multiple dosing of 125 mg bosentan twice daily at steady state. The adjusted geometric mean ratios (90% confidence interval (CI)) were 103% (86%-124%) and 99% (91%-107%) for C_max and AUC_0-tz of nintedanib, respectively (n=13), indicating that co-administration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib.
Concomitant treatment with oral hormonal contraceptives: In a dedicated pharmacokinetic study, female patients with SSc-ILD received a single dose of a combination of 30 μg ethinylestradiol and 150 μg levonorgestrel before and after twice daily dosing of 150 mg nintedanib for at least 10 days. The adjusted geometric mean ratios (90% confidence interval (CI)) were 117% (108%-127%; C_max) and 101% (93%-111%; AUC_0-tz) for ethinylestradiol and 101% (90%-113%; C_max) and 96% (93%-111%; AUC_0-tz) for levonorgestrel, respectively (n=15), indicating that co-administration of nintedanib has no relevant effect on the plasma exposure of ethinylestradiol and levonorgestrel.
Drug-Drug Interaction Potential: Metabolism: Drug-drug interactions between nintedanib and CYP substrates, CYP inhibitors, or CYP inducers are not expected, since nintedanib, BIBF 1202, and BIBF 1202 glucuronide did not inhibit or induce CYP enzymes preclinically nor was nintedanib metabolized by CYP enzymes to a relevant extent.
Transport: Nintedanib is a substrate of P-gp. For the interaction potential of nintedanib with this transporter, see Interactions. Nintedanib was shown to be not a substrate or inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2 or MRP-2 in vitro. Nintedanib was also not a substrate of BCRP. Only a weak inhibitory potential on OCT-1, BCRP, and P-gp was observed in vitro which is considered to be of low clinical relevance. The same applies for nintedanib being a substrate of OCT-1.
Toxicology: General toxicology: Single dose toxicity studies in rats and mice indicated a low acute toxic potential of nintedanib. In repeat dose toxicology studies in rats, adverse effects (e.g. thickening of epiphyseal plates, lesions of the incisors) were mostly related to the mechanism of action (i.e. VEGFR-2 inhibition) of nintedanib. These changes are known from other VEGFR-2 inhibitors and can be considered class effects.
Diarrhoea and vomiting accompanied by reduced food consumption and loss of body weight were observed in toxicity studies in non-rodents.
There was no evidence of liver enzyme increases in rats, dogs, and Cynomolgus monkeys. Mild liver enzyme increases which were not due to serious adverse effects such as diarrhoea were only observed in Rhesus monkeys.
Reproduction toxicity: Oncology: A study of male fertility and early embryonic development up to implantation in rats did not reveal effects on the male reproductive tract and male fertility.
In rats, embryo-foetal lethality and teratogenic effects were observed at exposure levels below human exposure at the maximum recommended human dose (MRHD) 200 mg twice daily. Effects on the development of the axial skeleton and on the development of the great arteries were also noted at subtherapeutic exposure levels.
In rabbits, embryo-foetal lethality and teratogenic effects comparable to those in rats were observed at an exposure slightly higher than in rats.
In rats, small amounts of radiolabelled nintedanib and/or its metabolites were excreted into the milk (≤0.5% of the administered dose).
From the 2-year carcinogenicity studies in mice and rats, there was no evidence for a carcinogenic potential of nintedanib.
Genotoxicity studies indicated no mutagenic potential for nintedanib.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): A study of male fertility and early embryonic development up to implantation in rats did not reveal effects on the male reproductive tract and male fertility.
In rats, embryo-foetal lethality and teratogenic effects were observed at exposure levels below human exposure at the maximum recommended human dose (MRHD) of 150 mg twice daily. Effects on the development of the axial skeleton and on the development of the great arteries were also noted at subtherapeutic exposure levels.
In rabbits, embryofoetal lethality and teratogenic effects comparable to those in rats were observed at an exposure slightly higher than in rats.
In rats, small amounts of radiolabelled nintedanib and/or its metabolites were excreted into the milk (≤0.5% of the administered dose).
From the 2-year carcinogenicity studies in mice and rats, there was no evidence for a carcinogenic potential of nintedanib.
Genotoxicity studies indicated no mutagenic potential for nintedanib.

Oncology: Nintedanib esilate (Ofev) is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after failure of first line chemotherapy.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Nintedanib esilate (Ofev) is indicated in adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF).
Nintedanib esilate (Ofev) is also indicated for the treatment of other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype (see Pharmacology: Pharmacodynamics: Clinical trials under Actions).
Nintedanib esilate (Ofev) is indicated for the treatment of Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD).

Adults: Oncology: Treatment with Nintedanib esilate (Ofev) should be initiated and supervised by a physician experienced in the use of anticancer therapies.
For posology, method of administration, and dose modifications of docetaxel, refer to the corresponding product information for docetaxel.
The recommended dose of Nintedanib esilate (Ofev) is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21-day docetaxel treatment cycle.
Nintedanib esilate (Ofev) must not be taken on the same day of docetaxel chemotherapy administration (=day 1).
The recommended maximum daily dose of 400 mg should not be exceeded.
Patients may continue therapy with Nintedanib esilate (Ofev) after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Treatment should be initiated by physicians experienced in the diagnosis and treatment of conditions for which Nintedanib esilate (Ofev) is indicated.
The recommended dose of Nintedanib esilate (Ofev) is 150 mg twice daily administered approximately 12 hours apart.
The recommended maximum daily dose of 300 mg should not be exceeded.
Dose Adjustments: Oncology: As initial measure for the management of adverse reactions (see Table 12 and Table 13) treatment with Nintedanib esilate (Ofev) should be temporarily interrupted until the specific adverse reaction has resolved to levels that allow continuation of therapy (to grade 1 or baseline). Nintedanib esilate (Ofev) treatment may be resumed at a reduced dose. Dose adjustments in 100 mg steps per day (i.e. a 50 mg reduction per dosing) based on individual safety and tolerability are recommended as described in Table 12 and Table 13.
In case of further persistence of the adverse reaction(s), i.e. if a patient does not tolerate 100 mg twice daily, treatment with Nintedanib esilate (Ofev) should be permanently discontinued.
In case of specific elevations of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) values to >3 x upper limit normal (ULN) in conjunction with an increase of total bilirubin to ≥2 x ULN and alkaline phosphatase (ALKP) <2 x ULN (see Table 13) treatment with Nintedanib esilate (Ofev) should be interrupted. Unless there is an alternative cause established, Nintedanib esilate (Ofev) should be permanently discontinued (see Precautions). (See Tables 12 and 13.)

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Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): In addition to symptomatic treatment if applicable, the management of adverse reactions (see Precautions and Adverse Reactions) of Nintedanib esilate (Ofev) could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy. Nintedanib esilate (Ofev) treatment may be resumed at the full dose (150 mg twice daily in adult patients) or a reduced dose (100 mg twice daily in adult patients). If an adult patient does not tolerate 100 mg twice daily, treatment with Nintedanib esilate (Ofev) should be discontinued.
In case of interruptions due to transaminase (AST or ALT) elevations >3x upper limit of normal (ULN), once transaminases have returned to baseline values, treatment with Nintedanib esilate (Ofev) may be reintroduced at a reduced dose (100 mg twice daily in adult patients) which subsequently may be increased to the full dose (150 mg twice daily in adult patients) (see Precautions and Adverse Reactions).
Special populations: Paediatric population: Oncology: The safety and efficacy of nintedanib in paediatric patients have not been studied in clinical trials for the oncology indication. Therefore, treatment of locally advanced, metastatic or recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology in children or adolescents with nintedanib is not recommended.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Treatment of paediatric patients with nintedanib for fibrosing Interstitial Lung Diseases (ILDs) is not registered.
Elderly patients (≥65 years): No overall differences in safety and efficacy were observed for elderly patients compared to patients aged below 65 years. No adjustment of the initial dosing is required in elderly patients (see Pharmacology: Pharmacokinetics under Actions).
Race: Based on population pharmacokinetic (PK) analyses, no a priori dose adjustments of Nintedanib esilate (Ofev) are necessary (see Special populations under Precautions and Pharmacology: Pharmacokinetics under Actions). Safety data for Black patients are limited.
Body weight: Based on population (PK) analyses, no a priori dose adjustments of Nintedanib esilate (Ofev) are necessary (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: Less than 1% of a single dose of nintedanib is excreted via the kidney (see Pharmacology: Pharmacokinetics under Actions). 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 (<30 mL/min CrCL).
Hepatic Impairment: Nintedanib is predominantly eliminated via biliary/faecal excretion (>90%). Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B, see Pharmacology: Pharmacokinetics: under Actions).
The safety and efficacy of nintedanib have not been investigated in patients with hepatic impairment classified as Child Pugh B and C. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Nintedanib esilate (Ofev) is not recommended see Pharmacology: Pharmacokinetics under Actions.
Oncology: No adjustment of the starting dose is needed for patients with mild hepatic impairment based on clinical data (Child Pugh A, see Precautions).
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): In adult patients with mild hepatic impairment (Child Pugh A), the recommended dose of Nintedanib esilate (Ofev) is 100 mg twice daily approximately 12 hours apart.
In patients with mild hepatic impairment (Child Pugh A), treatment interruption or discontinuation for management of adverse reactions should be considered.
Method of Administration: Nintedanib esilate (Ofev) capsules should be taken orally, preferably with food, swallowed whole with water, and should not be chewed. If a dose is missed, administration should resume at the next scheduled time at the recommended dose. If a dose is missed, the patient should not be given an additional dose.
Nintedanib esilate (Ofev) capsules may be taken with a small amount (teaspoonful) of cold or room temperature soft food, such as apple sauce or chocolate pudding, and must be swallowed unchewed immediately, to ensure the capsule stays intact.
The capsule should not be opened or crushed. If contact with the content of the capsule occurs, hands should be washed immediately and thoroughly.

There is no specific antidote or treatment for Nintedanib esilate (Ofev) overdose. The highest single dose of nintedanib administered in phase I studies was 450 mg once daily. In addition, 2 patients in the oncology programme had an overdose of maximum 600 mg twice daily (b.i.d) up to eight days. Observed adverse events were consistent with the known safety profile of nintedanib, i.e. increased liver enzymes and gastrointestinal symptoms. Both patients recovered from these adverse reactions.
In case of overdose, treatment should be interrupted and general supportive measures initiated as appropriate.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): In the INPULSIS trials, one patient was inadvertently exposed to a dose of 600 mg daily for a total of 21 days. A non-serious adverse event (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of other reported events.

Nintedanib esilate (Ofev) capsules is contraindicated in patients with known hypersensitivity to nintedanib, peanut or soya, or to any of the excipients (see Description).
Nintedanib esilate (Ofev) is contraindicated during pregnancy (see Use in Pregnancy & Lactation and Pharmacology: Toxicology under Actions).
Oncology: For contraindications of docetaxel refer to the corresponding product information for docetaxel.

Gastrointestinal Disorders: Oncology: Diarrhoea: Diarrhoea was the most frequently reported gastro-intestinal event and appeared in close temporal relationship with the administration of docetaxel (see Adverse Reactions). In the clinical trial LUME-Lung 1 (see Pharmacology: Pharmacodynamics: Clinical trials under Actions), the majority of patients had mild to moderate diarrhoea. 6.3% of the patients had diarrhoea of grade ≥3 in combination treatment compared to 3.6% treated with docetaxel alone. Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require interruption, dose reduction or discontinuation of therapy with Nintedanib esilate (Ofev) (see Dosage & Administration).
Nausea and vomiting: Nausea and vomiting, mostly of mild to moderate severity, were frequently reported gastrointestinal adverse events (see Adverse Reactions). If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction, treatment interruption or discontinuation of therapy with Nintedanib esilate (Ofev) (see Dosage & Administration) may be required.
Diarrhoea and vomiting may lead to dehydration with or without electrolyte disturbances which may progress to renal function impairment. In the event of dehydration, administration of electrolytes and fluids is required. Plasma levels of electrolytes should be monitored, if relevant gastrointestinal adverse events occur.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Diarrhoea: In the clinical trials (see Pharmacology: Pharmacodynamics: Clinical trials under Actions), diarrhoea was the most frequent gastro-intestinal event reported. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. In the INPULSIS trials in patients with IPF, diarrhoea was reported in 62.4% versus 18.4% of patients treated with Nintedanib esilate (Ofev) and placebo, respectively. Diarrhoea led to dose reduction in 10.7% of the patients and to discontinuation of Nintedanib esilate (Ofev) in 4.4% of the patients. In the INBUILD trial in patients with other chronic fibrosing ILDs with a progressive phenotype, diarrhoea was reported in 66.9% versus 23.9% of patients treated with Nintedanib esilate (Ofev) and placebo, respectively. Diarrhoea led to dose reduction of Nintedanib esilate (Ofev) in 16.0% of the patients and to discontinuation of Nintedanib esilate (Ofev) in 5.7% of the patients. In the SENSCIS trial in patients with SSc-ILD, diarrhoea was reported in 75.7% versus 31.6% of patients treated with Nintedanib esilate (Ofev) and placebo, respectively. Diarrhoea led to dose reduction of Nintedanib esilate (Ofev) in 22.2% of the patients and to discontinuation of Nintedanib esilate (Ofev) in 6.9% of the patients (see Adverse Reactions).
Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require dose reduction or treatment interruption. Nintedanib esilate (Ofev) treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with Nintedanib esilate (Ofev) should be discontinued.
Nausea and vomiting: Nausea and vomiting were frequently reported adverse events (see Adverse Reactions). In most patients with nausea and vomiting, the event was of mild to moderate intensity. In the INPULSIS trials, nausea led to discontinuation of Nintedanib esilate (Ofev) in 2.0% of patients and vomiting led to discontinuation in 0.8% of the patients. In the INBUILD trial, the frequency of nausea and vomiting leading to Nintedanib esilate (Ofev) discontinuation were 0.3% and 0.9%, respectively. In the SENSCIS trial, the frequency of nausea and vomiting leading to Nintedanib esilate (Ofev) discontinuation were 2.1% and 1.4%, respectively.
If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction or treatment interruption may be required. The treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe symptoms therapy with Nintedanib esilate (Ofev) should be discontinued.
Diarrhoea and vomiting may lead to dehydration with or without electrolyte disturbances which may progress to renal function impairment.
Neutropenia and Sepsis: Oncology: A higher frequency of neutropenia of CTCAE grade >3 was observed in patients treated with Nintedanib esilate (Ofev) in combination with docetaxel as compared to treatment with docetaxel alone. Subsequent complications such as sepsis or febrile neutropenia have been observed.
Blood counts should be monitored during therapy, in particular during the combination treatment with docetaxel. Frequent monitoring of complete blood counts should be performed at the beginning of each treatment cycle and around the nadir for patients receiving treatment with nintedanib in combination with docetaxel, and as clinically indicated after the administration of the last combination cycle.
Hepatic Function: The safety and efficacy of Nintedanib esilate (Ofev) has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore treatment with Nintedanib esilate (Ofev) is not recommended in such patients.
Oncology: Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A; see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cases of drug-induced liver injury have been observed with nintedanib treatment. In the postmarketing period, severe liver injury with fatal outcome has been reported. Elevations of liver enzymes (ALT, AST, ALKP, gamma-glutamyltransferase (GGT)) and bilirubin were reversible upon dose reduction or interruption in the majority of cases.
Transaminase, ALKP and bilirubin levels should be investigated upon initiation of the combination treatment with Nintedanib esilate (Ofev) plus docetaxel. The values should be monitored as clinically indicated or periodically during treatment, i.e. in the combination phase with docetaxel at the beginning of each treatment cycle and monthly in case Nintedanib esilate (Ofev) is continued as monotherapy after discontinuation of docetaxel.
If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with Nintedanib esilate (Ofev) may be required (see Table 13 under Dosage & Administration). Alternative causes of the liver enzyme elevations should be investigated and respective action should be taken as necessary.
In case of specific changes in liver values (AST/ALT >3 x ULN in conjunction with bilirubin ≥2 x ULN and ALKP <2 x ULN) treatment with Nintedanib esilate (Ofev) should be interrupted. Unless there is an alternative cause established, Nintedanib esilate (Ofev) should be permanently discontinued (see Table 13 under Dosage & Administration).
Female and Asian patients have a higher risk of elevations in liver enzymes.
Nintedanib exposure increased linearly with patient age and was inversely correlated to weight which may also result in a higher risk of developing liver enzyme elevations (see Pharmacology: Pharmacokinetics under Actions). Close monitoring is recommended in patients with these risk factors.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A). Adult patients with mild hepatic impairment (Child Pugh A) should be treated with a reduced dose of Nintedanib esilate (Ofev) (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cases of drug-induced liver injury have been observed with nintedanib treatment. In the postmarketing period, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcome, have been reported. The majority of hepatic events occur within the first three months of treatment. Therefore, hepatic transaminase and bilirubin levels should be investigated upon initiation of treatment with Nintedanib esilate (Ofev), at regular intervals during the first three months of treatment and periodically thereafter (e.g. at each patient visit) or as clinically indicated.
Elevations of liver enzymes (ALT, AST, ALKP, gamma-glutamyl-transferase (GGT)) and bilirubin were reversible upon dose reduction or interruption in the majority of cases. If transaminase (AST or ALT) elevations > 3 x upper limit of normal (ULN) are measured, dose reduction or interruption of the therapy with Nintedanib esilate (Ofev) is recommended and the patient should be monitored closely. Once transaminases have returned to baseline values, treatment with Nintedanib esilate (Ofev) may be re-increased to the full dose (150 mg twice daily) or reintroduced at a reduced dose daily (100 mg twice daily) which subsequently may be increased to the full dose (see Dosage & Administration). If any liver test elevations are associated with clinical signs or symptoms of liver injury, e.g. jaundice, treatment with Nintedanib esilate (Ofev) should be permanently discontinued. Alternative causes of the liver enzyme elevations should be investigated.
Adult patients with low body weight (<65 kg), Asian and female patients have a higher risk of elevations in liver enzymes.
Nintedanib exposure increased linearly with patient age, which may also result in a higher risk of developing liver enzyme elevations (see Pharmacology: Pharmacokinetics under Actions).
Close monitoring is recommended in patients with these risk factors.
Haemorrhage: Oncology: VEGFR inhibition might be associated with an increased risk of bleeding. In the clinical trial (LUME-Lung 1) with Nintedanib esilate (Ofev), the frequency of bleeding in both treatment arms was comparable. Mild to moderate epistaxis represented the most frequent bleeding event. There were no imbalances of respiratory or fatal bleedings and no intracerebral bleeding was reported. The majority of fatal bleeding events were tumour-associated.
In the post-marketing period non-serious and serious bleeding events, some of which were fatal, have been observed. In patients who experience grade 3/4 bleeding events, the benefits and risks of continuing treatment with Nintedanib esilate (Ofev) should be carefully weighed and discontinuation of Nintedanib esilate (Ofev) may be considered. If treatment with Nintedanib esilate (Ofev) is resumed, a reduced daily dose is recommended (see Table 12 under Dosage & Administration).
Patients with recent pulmonary bleeding (>2.5 mL of red blood) as well as patients with centrally located tumours with radiographic evidence of local invasion of major blood vessels or radiographic evidence of cavitary or necrotic tumours have been excluded from clinical trials. Therefore, it is not recommended to treat these patients with Nintedanib esilate (Ofev).
Brain metastasis: Stable brain metastasis: No increased frequency of cerebral bleeding in patients with adequately pre-treated brain metastases which were stable for ≥4 weeks before start of treatment with Nintedanib esilate (Ofev) was observed. However, such patients should be closely monitored for signs and symptoms of cerebral bleeding.
Active brain metastasis: Patients with active brain metastasis were excluded from clinical trials and are not recommended for treatment with Nintedanib esilate (Ofev).
Therapeutic anticoagulation: There are no data available for patients with inherited predisposition to bleeding or for patients receiving a full dose of anticoagulative treatment prior to start of treatment with Nintedanib esilate (Ofev). In patients on chronic low dose therapy with low molecular weight heparins or acetylsalicylic acid, no increased frequency of bleeding was observed. Patients who developed thromboembolic events during treatment and who required anticoagulant treatment were allowed to continue Nintedanib esilate (Ofev) and did not show an increased frequency of bleeding events. Patients taking concomitant anticoagulation, such as warfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, INR, or clinical bleeding episodes.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): VEGFR inhibition might be associated with an increased risk of bleeding.
In the clinical trials in adult patients with Nintedanib esilate (Ofev), the frequency of patients who experienced bleeding adverse events was slightly higher in patients treated with Nintedanib esilate (Ofev) or comparable between the treatment arms (Nintedanib esilate (Ofev) 10.3% versus placebo 7.8% for INPULSIS; Nintedanib esilate (Ofev) 11.1% versus placebo 12.7% for INBUILD; Nintedanib esilate (Ofev) 11.1% versus placebo 8.3% for SENSCIS). Non-serious epistaxis was the most frequent bleeding event reported. Serious bleeding events occurred with low frequencies in the 2 treatment groups (Nintedanib esilate (Ofev) 1.3% versus placebo 1.4% for INPULSIS; Nintedanib esilate (Ofev) 0.9% versus placebo 1.5% for INBUILD; Nintedanib esilate (Ofev) 1.4% versus placebo 0.7% for SENSCIS). Patients at known risk for bleeding including patients with inherited predisposition to bleeding or patients receiving a full dose of anticoagulative treatment were not included in clinical trials. Therefore, these patients should only be treated with Nintedanib esilate (Ofev) if the anticipated benefit outweighs the potential risk. In the post-marketing period non-serious and serious bleeding events, some of which were fatal, have been observed.
Arterial thromboembolic events: Use caution when treating patients with a higher cardiovascular risk including known coronary artery disease. Treatment interruption should be considered in patients who develop signs or symptoms of acute myocardial ischaemia.
Oncology: The frequency of arterial thromboembolic events was comparable between the two treatment arms in the phase III study 1199.13 (LUME-Lung 1). Patients with a recent history of myocardial infarction or stroke were excluded from this study. However, an increased frequency of arterial thromboembolic events was observed in patients with Idiopathic Pulmonary fibrosis (IPF) when treated with nintedanib monotherapy.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Patients with a recent history of myocardial infarction or stroke were excluded from the clinical trials.
In the clinical trials in adult patients, arterial thromboembolic events were infrequently reported (Nintedanib esilate (Ofev) 2.5% versus placebo 0.7% for INPULSIS: Nintedanib esilate (Ofev) 0.9% versus placebo 0.9% for INBUILD; Nintedanib esilate (Ofev) 0.7% versus placebo 0.7% for SENSCIS). In the INPULSIS trials, a higher percentage of patients experienced myocardial infarctions in the Nintedanib esilate (Ofev) group (1.6%) compared to the placebo group (0.5%) while adverse events reflecting ischaemic heart disease were balanced between the Nintedanib esilate (Ofev) and placebo groups. In the INBUILD and the SENSCIS trial myocardial infarction was observed with low frequency: Nintedanib esilate (Ofev) 0.9% versus placebo 0.9% for INBUILD; Nintedanib esilate (Ofev) 0% versus placebo 0.7% for SENSCIS.
Use caution when treating patients with a higher cardiovascular risk including known coronary artery disease. Treatment interruption should be considered in patients who develop signs or symptoms of acute myocardial ischaemia.
Venous thromboembolism: Oncology: Patients treated with Nintedanib esilate (Ofev) have an increased risk of venous thromboembolism including deep vein thrombosis. Patients should be closely monitored for thromboembolic events. Nintedanib esilate (Ofev) should be discontinued in patients with life-threatening venous thromboembolic reactions.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): In the clinical trials no increased risk of venous thromboembolism was observed in Nintedanib esilate (Ofev) treated patients. Due to the mechanism of action of nintedanib patients might have an increased risk of thromboembolic events.
Gastrointestinal perforations: Oncology: The frequency of gastrointestinal perforation was comparable between the treatment arms in the LUME-Lung 1 study. Due to the mechanism of action nintedanib patients might have an increased risk of gastrointestinal perforations. Cases of gastrointestinal perforations, some of which were fatal, have been reported in the post-marketing period. Particular caution should be exercised when treating patients with previous abdominal surgery or a recent history of a hollow organ perforation. Nintedanib esilate (Ofev) should therefore only be initiated at least 4 weeks after major, incl. abdominal, surgery. Therapy with Nintedanib esilate (Ofev) should be permanently discontinued in patients who develop gastrointestinal perforation.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): In the clinical trials no increased risk of gastrointestinal perforation was observed in Nintedanib esilate (Ofev) treated patients. Due to the mechanism of action nintedanib patients might have an increased risk of gastrointestinal perforations. Cases of gastrointestinal perforations, some of which were fatal, have been reported in the post-marketing period. Particular caution should be exercised when treating patients with previous abdominal surgery, or a recent history of a hollow organ perforation, previous history of peptic ulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs. Nintedanib esilate (Ofev) should therefore only be initiated at least 4 weeks after major, incl. abdominal, surgery. Therapy with Nintedanib esilate (Ofev) should be permanently discontinued in patients who develop gastrointestinal perforation.
Nephrotic range proteinuria: Very few cases of nephrotic range proteinuria have been reported post-marketing. Histological findings in individual cases were consistent with glomerular microangiopathy with or without renal thrombi. Reversal of symptoms has been observed after Nintedanib esilate (Ofev) was discontinued. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.
Wound healing complication: Based on the mechanism of action nintedanib may impair wound healing. No increased frequency of impaired wound healing was observed in the clinical trials. No dedicated studies investigating the effect of nintedanib on wound healing were performed. Treatment with Nintedanib esilate (Ofev) should therefore only be initiated or in case of perioperative interruption resumed based on clinical judgement of adequate wound healing.
Special Populations: Oncology: In the study 1199.13 (LUME-Lung 1), there was a higher frequency of serious adverse events in patients treated with Nintedanib esilate (Ofev) plus docetaxel with a body weight of less than 50 kg compared to patients with a weight ≥50 kg; however the number of patients with a body weight of less than 50 kg was small. Therefore, close monitoring is recommended in patients weighing <50 kg.
Soya lecithin: Nintedanib esilate (Ofev) soft capsules contain soya lecithin.
If the patient is allergic to peanut or soya, do not use this medicinal product.
Driving and Using Machines: No studies of the effects on the ability to drive and use machines have been performed.
Patients should be advised to be cautious when driving or using machines during treatment with Nintedanib esilate (Ofev).

Contraception: Nintedanib may cause foetal harm (see Pharmacology: Toxicology under Actions). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Nintedanib esilate (Ofev) and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of Nintedanib esilate (Ofev). Nintedanib does not relevantly affect the plasma exposure of ethinylestradiol and levonorgestrel (see Pharmacology: Pharmacokinetics under Actions). The efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhoea or other conditions where the absorption may be affected. Women taking oral hormonal contraceptives experiencing these conditions should be advised to use an alternative highly effective contraceptive measure.
Pregnancy: There is no information on the use of Nintedanib esilate (Ofev) in pregnant women, but preclinical studies in animals have shown reproductive toxicity of this drug (see Pharmacology: Toxicology under Actions). As nintedanib may cause foetal harm also in humans, it must not be applied during pregnancy (see Contraindications) and pregnancy testing must be conducted prior to treatment with Nintedanib esilate (Ofev) and during treatment as appropriate.
Female patients should be advised to notify their doctor or pharmacist if becoming pregnant during therapy with Nintedanib esilate (Ofev).
If the patient becomes pregnant while receiving Nintedanib esilate (Ofev) treatment must be discontinued and the patient should be apprised of the potential hazard to the foetus.
Lactation: There is no information on the excretion of nintedanib and its metabolites in human milk.
Pre-clinical studies showed that small amounts of nintedanib and its metabolites (≤0.5 % of the administered dose) were secreted into milk of lactating rats.
A risk to the newborns/infants cannot be excluded. Breastfeeding should be discontinued during treatment with Nintedanib esilate (Ofev).
Fertility: Oncology: Based on preclinical investigations, there is no evidence for impairment of male fertility (see Pharmacology: Toxicology under Actions). From subchronic and chronic toxicity studies, there is no evidence that female fertility in rats is impaired at a systemic exposure level comparable with that at the maximum recommended human dose (MRHD) of 200 mg twice daily (see Pharmacology: Toxicology under Actions).
Idiopathic Pulmonary Fibrosis, other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype (IPF) and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Based on preclinical investigations, there is no evidence for impairment of male fertility (see Pharmacology: Toxicology under Actions). From subchronic and chronic toxicity studies, there is no evidence that female fertility in rats is impaired at a systemic exposure level comparable with that at the maximum recommended human dose (MRHD) of 150 mg twice daily (see Pharmacology: Toxicology under Actions).
Oncology: For fertility, pregnancy and lactation information for docetaxel refer to the corresponding product information for docetaxel.

Summary of the safety profile: For the management of selected adverse reactions see Precautions.
Oncology: The safety data provided in the following are based on the global, double-blind randomised pivotal phase III trial 1199.13 (LUME-Lung 1) comparing treatment with Nintedanib esilate (Ofev) plus docetaxel against placebo plus docetaxel in patients with locally advanced, or metastatic, or recurrent NSCLC after first-line chemotherapy and based on data observed during the post-marketing period. The most frequently reported adverse reactions specific for Nintedanib esilate (Ofev) were diarrhoea, increased liver enzyme values (ALT and AST) and vomiting. Table 14 provides a summary of the Adverse Reactions by System Organ Class (SOC).
Clinical trials in adult patients: Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Nintedanib esilate (Ofev) has been studied in clinical trials including 1529 patients suffering from Idiopathic Pulmonary Fibrosis (IPF), 663 patients with other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype, and 576 patients with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD).
The safety data provided in the following are based on: Two phase III, randomised, double-blind, placebo-controlled trials comparing treatment with Nintedanib esilate (Ofev) 150 mg twice daily to placebo for 52 weeks (INPULSIS-1 and INPULSIS-2) in 1061 patients with IPF.
One phase III randomised, double-blind, placebo-controlled trial comparing treatment with Nintedanib esilate (Ofev) 150 mg twice daily to placebo for at least 52 weeks in 663 patients with other chronic fibrosing ILDs with a progressive phenotype (INBUILD).
One phase III randomized, double-blind, placebo-controlled trial comparing treatment with Nintedanib esilate (Ofev) 150 mg twice daily to placebo for at least 52 weeks in 576 patients with SSc-ILD (SENSCIS).
Data observed during the post-marketing experience.
In clinical trials, the most frequently reported adverse reactions associated with the use of Nintedanib esilate (Ofev) included diarrhoea, nausea and vomiting, abdominal pain, decreased appetite, weight decreased and hepatic enzyme increased.
The safety profile of Nintedanib esilate (Ofev) in a long term extension trial in patients with IPF, treated from 1 up to more than 5 years, was consistent with that observed in the phase III trials (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
Tabulated summary of adverse reactions: See Tables 14 and 15.

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Click on icon to see table/diagram/image

P-glycoprotein (P-gp): Nintedanib is a substrate of P-gp (see Pharmacology: Pharmacokinetics under Actions). Co-administration with the potent P-gp inhibitor ketoconazole increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on C_max in a dedicated drug-drug interaction study.
In a drug-drug interaction study with the potent P-gp inducer rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on C_max upon co-administration with rifampicin compared to administration of nintedanib alone.
If co-administered with Nintedanib esilate (Ofev), potent P‑gp inhibitors (e.g. ketoconazole or erythromycin) may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of nintedanib. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with Nintedanib esilate (Ofev) (see Dosage & Administration).
Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John's Wort) may decrease exposure to nintedanib. Selection of an alternate concomitant medication with no or minimal P-gp induction potential should be considered.
Food: Nintedanib esilate (Ofev) is recommended to be taken with food (see Pharmacology: Pharmacokinetics under Actions).
Cytochrome (CYP)-enzymes: Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways. Nintedanib and its metabolites, the free acid moiety BIBF 1202 and its glucuronide BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in preclinical studies (see Pharmacology: Pharmacokinetics under Actions). The likelihood of drug-drug interactions with nintedanib based on CYP metabolism is therefore considered to be low.
Co-administration with other drugs: Co-administration of nintedanib with oral hormonal contraceptives did not alter the pharmacokinetics of oral hormonal contraceptives to a relevant extent (see Pharmacology: Pharmacokinetics under Actions).
Oncology: Co-administration of nintedanib with docetaxel (75 mg/m²) did not alter the pharmacokinetics of either drug to a relevant extent.
Idiopathic Pulmonary Fibrosis, other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Co-administration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib (see Pharmacology: Pharmacokinetics under Actions).

Store at temperatures not exceeding 25°C.
Store in the original package in order to protect from moisture.

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