Ofev

OFEV 100 mg soft capsules: Peach-colored, opaque, oblong, soft gelatin capsules, marked in dark grey on one side with Boehringer Ingelheim company symbol and with "100", and containing a bright yellow viscous suspension.
1 capsule contains 100 mg of nintedanib (= free base) corresponding to 120.4 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).
OFEV 150 mg soft capsules: Brown-colored, opaque, oblong, soft gelatin capsules, marked in dark grey on one side with Boehringer Ingelheim company symbol and with "150", and containing a bright yellow viscous suspension.
1 capsule contains 150 mg of nintedanib (= free base) corresponding to 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).
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).

Pharmacotherapeutic group: Antineoplastic agents - Protein-tyrosine kinase inhibitor. ATC code: L01EX09.
Pharmacology: Mode of action: 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 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: 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: Idiopathic Pulmonary Fibrosis (IPF): The clinical efficacy of 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 randomised in a 3:2 ratio to treatment with 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 change 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 OFEV compared to patients receiving placebo. The treatment effect was consistent in both trials. See Table 1 for individual and pooled study results. (See Table 1.)

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The robustness of the effect of 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 OFEV on slowing disease progression. See Figure 1 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 1.)

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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 OFEV group as compared to placebo. Similar results were observed in analyses using a conservative threshold of 10%. See Table 2 for individual and pooled study results. (See Table 2.)

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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 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 OFEV compared with placebo, see Table 3.

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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 OFEV 150 mg bid. The deterioration of HRQoL was smaller in the 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 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 OFEV 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 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 OFEV compared to placebo, in the INPULSIS-1 trial there was no difference in 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 OFEV compared to placebo. See Table 4 for individual and pooled study results. (See Table 4.)

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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 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 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 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 OFEV (see Table 5).

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Supportive evidence from the phase II trial (1199.30) 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 an OFEV 150 mg bid dose group.
The primary endpoint, rate of decline in FVC over 52 weeks was lower in the 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 OFEV, indicating stable health-related quality of life. The estimated mean difference for 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 OFEV group (2.3%, N=86) compared to placebo (13.8%, N=87). The estimated hazard ratio of OFEV versus placebo was 0.16 (95% CI 0.04, 0.71; p=0.0054).
Long-term treatment with OFEV in patients with IPF (INPULSIS-ON): An open-label extension trial of OFEV included 734 patients with IPF. Some patients were treated with OFEV for more than 5 years. Patients who completed the 52-week treatment period in an INPULSIS trial received open-label OFEV treatment in the extension trial INPULSIS-ON. Median exposure time for patients treated with 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 OFEV in the INPULSIS phase III trials (-113.6 mL per year). The adverse event profile of 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 OFEV co-administered with oral sildenafil, compared to treatment with 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 OFEV alone was consistent with the decline in FVC in patients with less advanced disease and treated with OFEV in the INPULSIS phase III trials. The addition of sildenafil to OFEV did not provide significant benefit in terms of quality of life vs. OFEV alone. The safety and tolerability profile of 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 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 OFEV alone.
Additional data from the phase IV INJOURNEY trial with OFEV 150 mg twice daily and add-on pirfenidone: Concomitant treatment with OFEV and pirfenidone has been investigated in an exploratory open-label, randomised trial of OFEV 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times a day) compared to 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 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 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 OFEV 150 mg bid or matching placebo for at least 52 weeks. The median OFEV exposure over the whole trial was 17.4 months and the mean 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 OFEV compared to patients receiving placebo (Table 6) corresponding to a relative treatment effect of 57.0%. (See Table 6.)

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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 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 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 2.)

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The robustness of the effect of 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 3 shows the evolution of change in FVC from baseline over time in the treatment groups. (See Figure 3.)

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In addition, favourable effects of OFEV were observed on the adjusted mean absolute change from 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 decline in FVC % predicted no greater than 5%, was higher in the OFEV group as compared to placebo. Similar results were observed in analyses using a threshold of 10% (Table 7). (See Table 7.)

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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 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 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 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 OFEV compared to placebo (see Figure 4).

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Survival analysis: The proportion of patients who died over 52 weeks was 4.8% in the 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 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 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 OFEV. The proportion of patients with an event over 52 weeks was 25.6% in the 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 35.2% in the OFEV group and 48.3% 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 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 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 OFEV group compared with 7.81 in the placebo group. The adjusted mean difference between the groups in favour of 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 OFEV group compared with 4.25 in the placebo group. The adjusted mean difference between the groups in favour of 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 OFEV has been studied in patients with SSc-ILD in a double-blind, randomised, 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 randomised in a 1:1 ratio to receive either 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 OFEV exposure 15.4 months; mean 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 OFEV compared to patients receiving placebo (Table 8) corresponding to a relative treatment effect of 43.8%. (See Table 8.)

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The effect of 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 in FVC in mL at week 52 (Figure 5 and Table 9) and rate of decline in FVC in % predicted over 52 weeks (Table 10) providing further substantiation of the effects of OFEV on slowing progression of SSc-ILD. Furthermore, fewer patients in the OFEV group had an absolute FVC decline >5% predicted (20.6% in the 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 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 OFEV on slowing progression of SSc-ILD persisted beyond 52 weeks. (See Figure 5 and Tables 9 and 10.)

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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 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 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 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).
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.
Paediatric population: 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 hours; fed: 3.98 h).
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.
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: 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 error: 55%). For comparison, median observed nintedanib trough concentrations for 150 mg bid 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 a Population PK (PopPK) analysis 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. PopPK analyses indicated moderate effects on exposure to nintedanib depending on age, body weight, and race (see as follows). Based on the high inter-individual 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: In a dedicated pharmacokinetic study, concomitant treatment of OFEV with pirfenidone was investigated in patients with IPF. Group 1 received a single dose of 150 mg 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 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: In a dedicated pharmacokinetic study, concomitant treatment of OFEV with bosentan was investigated in healthy volunteers. Subjects received a single dose of 150 mg 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%; Cmax) and 101% (93% - 111%; AUC0-tz) for ethinylestradiol and 101% (90% - 113%; Cmax) and 96% (91% - 102%; AUC0-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, irreversible changes of enamel and dentin were observed in the continuously fast-growing incisors, but not in premolars or molars.
In addition, thickening of epiphyseal growth plates during bone growth phases was observed and was reversible after discontinuation. 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: 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, 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.

OFEV is indicated in adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF).
OFEV is also indicated for the treatment of other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype.
OFEV is indicated for the treatment of Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD).

Dosage: Adults: Treatment should be initiated by physicians experienced in the diagnosis and treatment of conditions for which OFEV is indicated.
The recommended dose of 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: In addition to symptomatic treatment if applicable, the management of adverse reactions (see Precautions, Adverse Reactions) of OFEV could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy. 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 OFEV should be discontinued.
If 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 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, Adverse Reactions.)
Special populations: Paediatric population: 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. Patients ≥75 years may be more likely to require dose reduction to manage adverse effects (see Pharmacology: Pharmacokinetics under Actions).
Race: Based on population pharmacokinetic (PK) analyses, no a priori dose adjustments of OFEV are necessary (see Special populations as previously mentioned, 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 OFEV are necessary in adult patients (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).
In adult patients with mild hepatic impairment (Child Pugh A), the recommended dose of 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.
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 OFEV is not recommended see Pharmacology: Pharmacokinetics under Actions.
Method of Administration: 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.
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 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 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.
In case of overdose, treatment should be interrupted and general supportive measures initiated as appropriate.

OFEV is contraindicated in patients with known hypersensitivity to nintedanib, peanut or soya or to any of the excipients (see Description).
OFEV is contraindicated during pregnancy (see Use in Pregnancy & Lactation and Pharmacology: Toxicology under Actions).

Gastrointestinal Disorders: 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 OFEV and placebo, respectively. Diarrhoea led to dose reduction of OFEV in 10.7% of the patients and to discontinuation of 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 OFEV and placebo, respectively. Diarrhoea led to dose reduction of OFEV in 16.0% of the patients and to discontinuation of 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 OFEV and placebo, respectively. Diarrhoea led to dose reduction of OFEV in 22.2% of the patients and to discontinuation of 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. OFEV treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily) (see Dosage & Administration). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with 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 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 OFEV discontinuation were 0.3% and 0.9%, respectively. In the SENSCIS trial, the frequency of nausea and vomiting leading to 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) (see Dosage & Administration). In case of persisting severe symptoms therapy with OFEV should be discontinued.
Diarrhoea and vomiting may lead to dehydration with or without electrolyte disturbances which may progress to renal function impairment.
Hepatic Function: The safety and efficacy of OFEV has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore treatment with OFEV is not recommended in such patients.
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 OFEV (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cases of drug-induced liver injury have been observed with nintedanib treatment. In the post-marketing 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 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 >3x upper limit of normal (ULN) are measured, dose reduction or interruption of the therapy with OFEV is recommended and the patient should be monitored closely. Once transaminases have returned to baseline values, treatment with OFEV may be re-increased to the full dose (150 mg twice daily) or reintroduced at a reduced dose (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 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: Vascular endothelial growth factor receptor (VEGFR) inhibition might be associated with an increased risk of bleeding.
In the clinical trials in adult patients with OFEV, the frequency of patients who experienced bleeding adverse events was slightly higher in patients treated with OFEV or comparable between the treatment arms (OFEV 10.3% versus placebo 7.8% for INPULSIS; OFEV 11.1% versus placebo 12.7% for INBUILD; 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 (OFEV 1.3% versus placebo 1.4% for INPULSIS; OFEV 0.9% versus placebo 1.5% for INBUILD; 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 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: 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 (OFEV 2.5% versus placebo 0.7% for INPULSIS; OFEV 0.9% versus placebo 0.9% for INBUILD; OFEV 0.7% versus placebo 0.7% for SENSCIS). In the INPULSIS trials, a higher percentage of patients experienced myocardial infarctions in the OFEV group (1.6%) compared to the placebo group (0.5%), while adverse events reflecting ischaemic heart disease were balanced between the OFEV and placebo groups. In the INBUILD and the SENSCIS trial myocardial infarction was observed with low frequency: OFEV 0.9% versus placebo 0.9% for INBUILD; 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: In the clinical trials, no increased risk of venous thromboembolism was observed in OFEV treated patients. Due to the mechanism of action of nintedanib patients might have an increased risk of thromboembolic events.
Gastrointestinal perforations: In the clinical trials, no increased risk of gastrointestinal perforation was observed in 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, a recent history of a hollow organ perforation, previous history of peptic ulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs. OFEV should therefore only be initiated at least 4 weeks after major, incl. abdominal surgery. Therapy with 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 OFEV was discontinued.
Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.
Posterior reversible encephalopathy syndrome (PRES): Very few cases of posterior reversible encephalopathy syndrome (PRES) have been reported post-marketing.
PRES is a neurological disorder which can present with headache, visual disturbances, seizure, lethargy, confusion and other neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES.
If PRES is suspected, nintedanib treatment must be discontinued. The safety of reinitiating nintedanib therapy in patients previously experiencing PRES is not known.
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 OFEV should therefore only be initiated or - in case of perioperative interruption - resumed based on clinical judgement of adequate wound healing.
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 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 OFEV and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of 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 OFEV in pregnant women, but pre-clinical 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 OFEV and during treatment as appropriate.
Female patients should be advised to notify their doctor or pharmacist if becoming pregnant during therapy with OFEV.
If the patient becomes pregnant while receiving 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 OFEV.
Fertility: 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).

Summary of the safety profile: Clinical trials in adult patients: 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 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 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 randomised, double-blind, placebo-controlled trial comparing treatment with 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 OFEV included diarrhoea, nausea and vomiting, abdominal pain, decreased appetite, weight decreased and hepatic enzyme increased.
The safety profile of 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).
For the management of selected adverse reactions see Precautions. (See Table 11.)

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 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 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: 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 bosentan did not alter the pharmacokinetics of nintedanib (see Pharmacology: Pharmacokinetics under Actions).
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).

Do not store above 25°C. Store in the original package in order to protect from moisture.

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