Ofev

INSTRUCTIONS for medical use of the medicinal product OFEV® (OFEV®)

Composition:

Active substance: nintedanib;

1 capsule contains 100 mg or 150 mg of nintedanib (as esilate);

Excipients: medium-chain triglycerides, hard fat, lecithin (soy) (E 322);

Capsule shell: gelatin, glycerol 85%, titanium dioxide (E 171), iron oxide red (E 172), iron oxide yellow (E 172);

Black ink for capsule marking: shellac, ethanol, propylene glycol (E 1520), iron oxide black (E 172).

Pharmaceutical form. Soft capsules.

Main physicochemical properties:

OFEV, soft capsules 100 mg

Elongated opaque soft gelatin capsules of peach color, with the logo of «Boehringer Ingelheim» and the marking «100» printed in black ink on one side.

The capsules contain a viscous, bright yellow suspension.

OFEV, soft capsules 150 mg

Elongated opaque soft gelatin capsules of brown color, with the logo of «Boehringer Ingelheim» and the marking «150» printed in black ink on one side.

The capsules contain a viscous, bright yellow suspension.

Pharmacotherapeutic group. Antineoplastic agents. Protein kinase inhibitors.

ATC code L01EX09.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Nintedanib is a low-molecular-weight tyrosine kinase inhibitor that blocks receptors, including 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 (lymphocyte-specific protein tyrosine kinase), Lyn (protein tyrosine kinase), Src (proto-oncogene protein tyrosine kinase), and CSF1R (colony-stimulating factor 1 receptor). Nintedanib competitively interacts with the adenosine triphosphate (ATP)-binding site of these kinases and blocks intracellular signal transduction cascades shown to be involved in the pathogenesis of fibrotic tissue remodeling in interstitial lung diseases.

Pharmacodynamic effects

In in vitro studies using human cells, nintedanib was shown to inhibit processes involved in the initiation of fibrotic pathogenesis, release of profibrotic mediators from peripheral blood mononuclear cells, and polarization of macrophages toward alternatively activated macrophages. Nintedanib has been demonstrated to suppress fundamental processes in organ fibrosis, including fibroblast proliferation and migration, transformation into the active myofibroblast phenotype, and extracellular matrix secretion. In animal studies across several models of idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc-ILD), interstitial lung disease (ILD), ILD associated with rheumatoid arthritis (RA-ILD), and fibrosis of other organs, nintedanib demonstrated anti-inflammatory and antifibrotic effects in the lungs, skin, heart, kidneys, and liver. Nintedanib also showed vascular activity. It reduced dermal microvascular endothelial cell apoptosis and attenuated pulmonary vascular remodeling by decreasing vascular smooth muscle cell proliferation, pulmonary vessel wall thickness, and the proportion of occluded pulmonary vessels.

Clinical efficacy and safety

Idiopathic pulmonary fibrosis (IPF)

The clinical efficacy of nintedanib was evaluated in patients with IPF in two randomized, double-blind, placebo-controlled phase III trials with identical design (INPULSIS-1 (1199.32) and INPULSIS-2 (1199.34)). Patients with baseline predicted forced vital capacity (FVC) < 50% or diffusing capacity for carbon monoxide (DLCO, corrected for hemoglobin) < 30% of predicted value at baseline were excluded from the study. Patients were randomized in a 3:2 ratio to receive either OFEV 150 mg or placebo, administered twice daily for 52 weeks.

The primary endpoint was the annual rate of decline in forced vital capacity (FVC). Key secondary endpoints included change from baseline in total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52 and time to first acute exacerbation of IPF.

Annual rate of decline in FVC

The annual rate of decline in FVC (in mL) showed a significant reduction in patients receiving nintedanib compared to those receiving placebo. The treatment effect was consistent across both studies (see Table 1).

Table 1

Annual rate of decline in FVC in the INPULSIS-1, INPULSIS-2, and pooled data in the treated patient population

In a sensitivity analysis assuming that patients who were missing data at week 52 had a decline in FVC after the last recorded value similar to that observed in all placebo-treated patients, the adjusted difference in the annual rate of FVC decline between the nintedanib and placebo groups was 113.9 mL/year (95% CI 69.2, 158.5) in the INPULSIS-1 trial and 83.3 mL/year (95% CI 37.6, 129.0) in the INPULSIS-2 trial.

Figure 1 shows the time course of change from baseline in both treatment groups, based on a pooled analysis of data from the INPULSIS-1 and INPULSIS-2 trials.

Figure 1. Mean (SEM) observed change in FVC over time from baseline (mL), pooled data from INPULSIS-1 and INPULSIS-2.

Analysis of data in patients who responded to treatment in terms of FVC

In both INPULSIS trials, the percentage of patients who responded to treatment in terms of FVC—defined as patients in whom the absolute calculated decline in FVC did not exceed 5% (a threshold associated with increased mortality risk in IPF)—was significantly higher in the nintedanib group than in the placebo group. Similar results were observed when analyzing data using the conventional threshold of 10% (see Table 2).

Table 2

Percentage of patients who responded to treatment in terms of FVC at week 52 in INPULSIS-1, INPULSIS-2, and pooled data in the treated patient population

1Patients who responded to treatment were those with an absolute decline in FEV1 of no more than 5 or 10% from the calculated FEV1 value in %, depending on the threshold value, assessed at week 52.

2Based on logistic regression.

Time to disease progression (absolute decline in calculated FEV1 value in % of ≥10% or death)

In both INPULSIS trials, a clinically meaningful reduction in the risk of disease progression was demonstrated in patients receiving nintedanib compared to those receiving placebo. In the pooled analysis, the hazard ratio was 0.60, indicating a 40% reduction in the risk of disease progression in patients treated with nintedanib compared to those receiving placebo.

Table 3

Percentage of patients with absolute decline in calculated FEV1 value in % of ≥10% or death (events) over 52 weeks and time to disease progression in the INPULSIS-1, INPULSIS-2, and pooled data within the treated patient population

Change from baseline in total SGRQ score at week 52

In the pooled analysis of the INPULSIS trials, baseline SGRQ scores were 39.51 in the nintedanib group and 39.58 in the placebo group. The adjusted mean change in total SGRQ score at week 52 from baseline was smaller in the nintedanib group (3.53) compared to the placebo group (4.96), with a between-group treatment difference of -1.43 (95% CI: -3.09, 0.23; p = 0.0923). Overall, the effect of nintedanib on health-related quality of life, as measured by the total SGRQ score, was not significant and showed less deterioration compared to placebo.

Time to first acute exacerbation of IPF

In the pooled analysis of the INPULSIS trials, patients receiving nintedanib had a numerically lower risk of first acute exacerbation compared to those receiving placebo (see Table 4).

Table 4

Percentage of patients with acute exacerbations of IPF (events) over 52 weeks and time to first acute exacerbation based on investigator-reported data from the INPULSIS-1, INPULSIS-2, and pooled analysis in the treated patient population

Sensitivity analysis showed that the percentage of patients who had at least one expert-adjudicated exacerbation during 52 weeks was lower in the nintedanib group (1.9% of patients) than in the placebo group (5.7% of patients). In the time-to-first adjudicated exacerbation analysis using pooled data, a hazard ratio (HR) of 0.32 (95% CI 0.16, 0.65; p = 0.0010) was derived. This indicates that the risk of the first IPF exacerbation was statistically significantly lower in the nintedanib group than in the placebo group at any time point.

Survival analysis

In the pooled analysis of survival data based on pre-specified variables from the INPULSIS trials, all-cause mortality over the 52-week period was lower in the nintedanib group (5.5%) than in the placebo group (7.8%). In the time-to-death analysis, an HR of 0.70 (95% CI 0.43, 1.12; p = 0.1399) was determined. Results for all survival endpoints (such as on-treatment mortality and mortality due to respiratory events) demonstrated a consistent numerical advantage in favor of nintedanib.

Table 5

All-cause mortality (events) over 52 weeks in the INPULSIS-1, INPULSIS-2, and pooled data across the treated patient population

Long-term treatment with OFEV in patients with IPF (INPULSIS-ON)

A total of 734 patients with IPF participated in the open-label extension study of OFEV. Patients who had completed the 52-week treatment period in the INPULSIS trials received open-label treatment with OFEV in the INPULSIS-ON extension study. The median duration of exposure for patients who received OFEV in both studies (INPULSIS and INPULSIS-ON) was 44.7 months (range: 11.9–68.3). Investigational efficacy endpoints included annual rates of decline in FVC over 192 weeks, which was -135.1 (5.8) mL/year in all treated patients, consistent with the annual rate of FVC decline observed in patients receiving OFEV in the phase III INPULSIS trials (-113.6 mL/year). The safety profile of OFEV in the INPULSIS-ON study was consistent with the safety profile observed in the phase III INPULSIS trials.

Patients with IPF and severe impairment of lung function (INSTAGE)

INSTAGE was a multicenter, multinational, prospective, randomized, double-blind, parallel-group clinical trial of 24 weeks' duration involving patients with IPF and severe impairment of lung function (DLCO ≤ 35%). A total of 136 patients received monotherapy with OFEV. The result for the primary endpoint showed a reduction in the total score of the St. George's Respiratory Questionnaire (SGRQ) by -0.77 units at week 12, based on the adjusted mean change from baseline. A post hoc comparison demonstrated that the decline in forced vital capacity (FVC) in these patients was consistent with the FVC decline observed in patients with less advanced disease who received OFEV during the phase III INPULSIS trials.

The safety and tolerability profile of OFEV in patients with IPF and severe impairment of lung function was consistent with that observed in the phase III INPULSIS trials.

Additional data from the phase IV INJOURNEY study evaluating OFEV 150 mg twice daily in combination with pirfenidone

Concomitant treatment with nintedanib and pirfenidone was evaluated in an exploratory, open-label, randomized 12-week study comparing nintedanib 150 mg twice daily plus pirfenidone as add-on therapy (dose titrated up to 801 mg three times daily) versus nintedanib 150 mg twice daily as monotherapy in 105 randomized patients. The primary endpoint was the percentage of patients experiencing gastrointestinal adverse events at 12 weeks compared to baseline. Gastrointestinal events were frequent, consistent with the established safety profiles of each component. The most common adverse events were diarrhea, nausea, and vomiting in patients receiving pirfenidone in combination with nintedanib, compared to those receiving nintedanib as monotherapy. Mean absolute changes in FVC (forced vital capacity) from baseline at 12 weeks were –13.3 (17.4) mL in patients receiving nintedanib and pirfenidone as add-on therapy (n = 48), compared to –40.9 (31.4) mL in patients receiving nintedanib as monotherapy (n = 44).

Other chronic fibrosing interstitial lung diseases (ILD) with a progressive phenotype

The clinical efficacy of nintedanib was evaluated in patients with other chronic fibrosing interstitial lung diseases with a progressive phenotype in a phase III, double-blind, randomized, placebo-controlled trial (INBUILD). Patients with IPF were excluded. Patients with a clinical diagnosis of chronic fibrosing ILD were enrolled if they had relevant fibrosis (characteristic fibrotic features >10%) on high-resolution computed tomography (HRCT) and clinical evidence of disease progression (decline in FVC ≥10%, decline in FVC ≥5% and <10% with worsening symptoms or HRCT findings, or worsening symptoms and HRCT findings within 24 months prior to screening). Patients were required to have FVC ≥45% of predicted and DLCO between 30% and <80% of predicted. Patients had to demonstrate disease progression despite treatment considered appropriate by investigators according to clinical practice for the respective ILD.

A total of 663 patients were randomized in a 1:1 ratio to receive either 150 mg of the study drug twice daily or matching placebo for a minimum of 52 weeks. The median duration of exposure to OFEV during the entire study was 17.4 months, with a mean duration of exposure of 15.6 months. Randomization was stratified based on HRCT pattern of fibrotic changes as determined by central expert readers. A total of 412 patients with an HRCT pattern consistent with usual interstitial pneumonia (UIP) and 251 patients with other HRCT patterns of fibrotic changes were randomized. For analysis in this study, two primary populations were defined: all patients (overall population) and patients with an HRCT pattern consistent with UIP. Patients with other HRCT patterns of fibrotic changes represented an additional population.

The primary endpoint was the annual rate of decline in forced vital capacity (FVC) (mL) over 52 weeks. Key secondary endpoints included absolute change from baseline in the King's Brief Interstitial Lung Disease questionnaire (K-BILD) score at 52 weeks, time to first acute exacerbation of ILD or death over 52 weeks, and time to death over 52 weeks.

Patients had a mean age (standard deviation [SD; min–max]) of 65.8 (9.8; 27–87) years and a mean FVC of 69.0% of predicted (15.6; 42–137). The main clinical ILD diagnoses represented in the study were hypersensitivity pneumonitis (26.1%), autoimmune ILD (25.6%), idiopathic nonspecific interstitial pneumonia (18.9%), unclassified idiopathic interstitial pneumonia (17.2%), and other ILDs (12.2%).

Annual rate of FVC decline

The annual rate of FVC decline (mL) over 52 weeks demonstrated a significant reduction in patients receiving OFEV compared to those receiving placebo (Table 6), corresponding to a relative treatment effect of 57.0%.

Table 6

Annual rate of FVC decline (mL) over 52 weeks

1 Based on a random regression of coefficients with fixed categorical treatment effect, HRCT patterns, fixed time effect, baseline FVC [ml], as well as accounting for treatment-by-time interaction and baseline-by-time interaction.

Similar results were observed in the secondary population of patients with UIP pattern on HRCT. The treatment effect was consistent in the additional population of patients with other fibrotic patterns on HRCT (p-value for interaction 0.2268) (Fig. 2).

Fig. 2. Diagram of annual rate of decline in FVC (ml) over 52 weeks in patient populations.

The effect of OFEV on reducing the annual rate of decline in FVC was confirmed by all pre-specified sensitivity analyses; consistent results were observed in pre-specified efficacy subgroups: by sex, age, race, baseline FVC (% predicted), and primary clinical diagnosis of ILD.

Figure 3 shows the evolution of change in FVC from baseline in treatment groups.

Fig. 3. Mean LS means (Least Squares means) of observed change in FVC from baseline (ml) over 52 weeks.

Additionally, favorable effects of OFEV were observed on adjusted mean absolute change in FVC (% predicted) compared to baseline at week 52. The adjusted mean value of absolute change in FVC (% predicted) from baseline to week 52 was lower in the nintedanib group (-2.62%) than in the placebo group (-5.86%). The adjusted mean difference between treatment groups was 3.24 (95% CI: 2.09; 4.40; nominal p < 0.0001).

Analysis of patients achieving therapeutic benefit based on FVC

The proportion of patients achieving therapeutic benefit based on FVC, defined as patients with a relative decline in FVC of no more than 5% of predicted, was higher in the OFEV group compared to placebo. Similar results were observed in analyses using a 10% threshold (Table 7).

Table 7

Annual rate of decline in FVC (ml) over 52 weeks

1 Patients who achieved the therapeutic effect, assessed by the FEV1 parameter, were those who did not have a relative decline in FEV1 (% of predicted) greater than 5% or greater than 10%, depending on the threshold criteria, and with FEV1 assessment at week 52 (patients with missing data at week 52 were considered not to have achieved the therapeutic effect).

2 Based on a logistic regression model with continuous covariate baseline FEV1 (%) and binary covariate HRCT pattern.

Time to first acute exacerbation of IPF or death

Throughout the study, the proportion of patients who experienced at least one first acute exacerbation of IPF or death was 13.9% in the Ofev group and 19.6% in 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 exacerbation of IPF or death in patients receiving Ofev compared to those receiving placebo (Fig. 4).

2 r/d – twice daily

Fig. 4. Time to first acute exacerbation of IPF or death.

Survival analysis

The risk of death was lower in the Ofev treatment 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 those receiving placebo.

Time to disease progression (absolute decline in FEV1 (% of predicted) ≥ 10%) or death

In the INBUILD study, the risk of disease progression (absolute decline in FEV1 (% of predicted) ≥ 10%) or death was lower in patients receiving Ofev. The proportion of patients with the defined event was 40.4% in the 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 in the risk of progression (absolute decline in FEV1 (% of predicted) ≥ 10%) or death in patients receiving Ofev compared to those receiving placebo.

Quality of life

Adjusted mean change from baseline in the total K-BILD score at week 52 was -0.79 units in the placebo group and 0.55 in the Ofev group. The difference between treatment groups was 1.34 (95% CI: -0.31; 2.98; nominal p = 0.1115).

Adjusted mean absolute change from baseline in dyspnea symptoms according to the L-PF questionnaire at week 52 was 4.28 in the Ofev group compared to 7.81 in the placebo group. The adjusted mean difference between groups in favor of Ofev was -3.53 (95% CI: -6.14; -0.92; nominal p = 0.0081). Adjusted mean absolute change from baseline in cough symptoms according to the L-PF questionnaire at week 52 was -1.84 in the Ofev group compared to 4.25 in the placebo group. The adjusted mean difference between groups in favor of Ofev was -6.09 (95% CI: -9.65; -2.53; nominal p = 0.0008).

Interstitial lung disease associated with systemic sclerosis (systemic scleroderma) (SSc-ILD)

The clinical efficacy of nintedanib was evaluated in patients with SSc-ILD in a double-blind, randomized, placebo-controlled phase III trial (SENSCIS). Patients had SSc-ILD diagnosed based on the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for systemic sclerosis and high-resolution computed tomography (HRCT) of the chest within the previous 12 months. A total of 580 patients were randomized in a 1:1 ratio to receive either Ofev 150 mg twice daily or placebo for a minimum of 52 weeks. Of these, 576 patients received treatment. Randomization was stratified by anti-topoisomerase antibody (ATA) status. Individual patients remained on treatment in a blinded manner up to 100 weeks (median exposure to Ofev 15.4 months; mean exposure to Ofev 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 modified Rodnan skin score (mRSS) at week 52 and absolute change from baseline in total score of the St. George's Respiratory Questionnaire (SGRQ) at week 52.

In the overall population, 75.2% of patients were female. Mean (standard deviation (SD), min.–max.) age was 54 (12.2; 20–79) years. Overall, 51.9% of patients had diffuse cutaneous systemic sclerosis (dcSSc); 48.1% had limited cutaneous systemic sclerosis (lcSSc). Mean (SD) time from onset of the first non-Raynaud symptom was 3.49 (1.7) years. 49.0% of patients received stable mycophenolate therapy at baseline. The safety profile in patients who received or did not receive mycophenolate at baseline was similar.

Annual rate of decline in FVC

The annual rate of decline in FVC (mL) over 52 weeks was significantly reduced by 41.0 mL in patients receiving Ofev compared to those receiving placebo (Table 8), corresponding to a relative treatment effect of 43.8%.

Table 8

Annual rate of decline in FVC (mL) over 52 weeks

1 Based on a random regression of coefficients with fixed categorical treatment effect, ATA status, patient sex, fixed time effect, baseline FVC (ml), age and height of the patient, as well as accounting for the dependence of treatment efficacy on time and the dependence of changes from baseline over time. A random effect was included for individual patient visit time and time. Within-subject errors were modeled using an unstructured variance-covariance matrix. Between-subject variability was modeled using a variance-covariance matrix with variance components.

The effect of OFEV on reducing the annual rate of FVC decline was consistent in pre-specified sensitivity analyses; heterogeneity was not observed in pre-specified patient subgroups (e.g., by age, sex, and use of mycophenolate).

Furthermore, similar effects were observed for other lung function endpoints, particularly change in FVC at week 52 (Figure 5 and Table 9) from baseline and predicted rate of FVC decline in % over 52 weeks (Table 10), providing additional support for the effect of OFEV in slowing the progression of SSc-ILD. In addition, fewer patients in the OFEV group experienced an absolute FVC decline of >5% (20.6% in the OFEV group vs. 28.5% in the placebo group, HR=0.65, p=0.0287). Relative FVC decline in ml of >10% was similar between groups (16.7% in the OFEV group vs. 18.1% in the placebo group, HR=0.91, p=0.6842). In these analyses, missing FVC values at week 52 were imputed using the worst post-baseline value during treatment.

An exploratory analysis of data up to 100 weeks (maximum treatment duration in the SENSCIS trial) shows that the treatment effect of OFEV in slowing the progression of SSc-ILD is maintained beyond 52 weeks.

Figure 5. Mean (SE) observed change in FVC from baseline (ml) over 52 weeks.

Table 9

Absolute change in FVC (ml) from baseline at week 52

1 Based on a mixed-effects model for repeated measures (MMRM) with fixed categorical effects of ATA status, visit, treatment-by-visit interaction, baseline-by-visit interaction, patient age, sex, and height. Visit was treated as a repeated measure. Within-subject errors were modeled using an unstructured variance-covariance matrix. Adjusted mean was based on the total number of all analyzed patients in the model (not only those with measurements at baseline and Week 52).

Table 10

Annual rate of FEV1 decline (%) over 52 weeks

1 Based on random regression of coefficients with fixed categorical treatment effect, ATA status, fixed constant time effect, baseline FEV1 (% predicted), as well as accounting for treatment efficacy dependence on time and dependence of changes from baseline on time. Random effects were included for patient-specific measurement time and time. Within-subject errors were modelled using an unstructured variance-covariance matrix. Inter-individual variability was modelled using a variance-covariance matrix with variance components.

Change from baseline in modified Rodnan skin score (mRSS) at week 52

Adjusted mean absolute change from baseline in mRSS at week 52 was similar in the OFEV treatment group (-2.17 (95% CI -2.69, -1.65)) and the placebo group (-1.96 (95% CI -2.48, -1.45)). Adjusted mean difference between treatment groups was -0.21 (95% CI -0.94, 0.53; p = 0.5785).

Change from baseline in total Saint George's Respiratory Questionnaire (SGRQ) score at week 52

Adjusted mean absolute change from baseline in total SGRQ score at week 52 was similar in the OFEV treatment group (0.81 (95% CI -0.92, 2.55)) and the placebo group (-0.88 (95% CI -2.58, 0.82)). Adjusted mean difference between treatment groups was 1.69 (95% CI -0.73, 4.12; p = 0.1711).

Survival analysis

Mortality rate throughout the entire study period was similar in the OFEV treatment group (N = 10; 3.5%) and the placebo group (N = 9; 3.1%). In the analysis of time to death throughout the entire study period, a hazard ratio (HR) of 1.16 (95% CI 0.47, 2.84; p = 0.7535) was determined.

QT interval

In a dedicated study involving patients with renal cell carcinoma, QT interval/QT complex measurements were performed; these measurements showed that a single oral dose of 200 mg of nintedanib, as well as multiple oral doses of 200 mg nintedanib administered twice daily for 15 days, did not prolong the QT interval corrected by Fridericia’s formula.

Children.

OFEV has not been studied in pediatric patients with IPF.

Pharmacokinetics.

Absorption

Maximum plasma concentration of nintedanib is reached approximately 2–4 hours after oral administration of the soft gelatin capsule formulation with food (range 0.5–8 hours). Absolute bioavailability of a 100 mg dose in healthy volunteers is 4.69% (90% CI 3.615–6.078). Absorption and bioavailability are reduced due to transporter effects and significant presystemic metabolism. Nintedanib exposure increases proportionally with dose (in dose ranges of 50–450 mg once daily and 150–300 mg twice daily). Steady-state plasma concentrations are achieved within one week after initiation of treatment.

Exposure to nintedanib increases by approximately 20% when administered after food compared to administration in the fasted state (CI 95.3–152.5%), and absorption is delayed (median time to reach maximum plasma concentration (tmax) is 2.00 hours in the fasted state; 3.98 hours after food).

Distribution

Nintedanib distribution follows a two-phase kinetic pattern. After intravenous infusion, a large volume of distribution (Vss) is observed during the terminal phase: 1050 L, geometric coefficient of variation (gCV) 45.0%.

In vitro, binding of nintedanib to human plasma proteins is considered significant, with a bound fraction of 97.8%. Serum albumin is the main protein involved in binding. Nintedanib is predominantly distributed in plasma, with a blood-to-plasma ratio of 0.869.

Biotransformation

The primary reaction involved in nintedanib metabolism is hydrolytic cleavage by esterases, leading to the formation of the free acid metabolite of nintedanib (BIBF 1202). Subsequently, BIBF 1202 is glucuronidated by uridine-5’-diphosphate-glucuronosyltransferase (UGT) enzymes, specifically UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10, forming the BIBF 1202 glucuronide.

CYP-mediated biotransformation of nintedanib occurs to only a minor extent; the main isoenzyme involved is CYP 3A4. In a human ADME study, the main CYP-mediated metabolite was not detected in plasma. In vitro studies indicate that CYP-dependent metabolism accounts for approximately 5%, whereas esterase-mediated cleavage accounts for 25%. Nintedanib, BIBF 1202, and BIBF 1202 glucuronide did not inhibit or induce CYP isoenzymes in vitro or in preclinical studies. Therefore, drug interactions between nintedanib and CYP substrates, CYP inhibitors, or CYP inducers are not expected.

Elimination

Total plasma clearance after intravenous infusion is high (1390 mL/min, gCV 28.8%). Renal excretion of unchanged active substance within 48 hours after oral administration of nintedanib is approximately 0.05% of the dose (gCV 31.5%), and after intravenous administration, approximately 1.4% (gCV 24.2%); renal clearance is 20 mL/min (gCV 32.6%). After oral administration of [14C]-nintedanib, the radioactive material was predominantly excreted via bile and found in feces (93.4% of dose, gCV 2.61%). The renal excretion fraction in total clearance is low (0.649% of dose (gCV 26.3%)). Elimination is considered complete (more than 90%) within 4 days after administration. Terminal half-life of nintedanib ranges from 10 to 15 hours (gCV approximately 50%).

Linearity/non-linearity

Pharmacokinetics (PK) of nintedanib can be assumed to be linear over time (i.e., single-dose data can be extrapolated to multiple-dose use). Accumulation-derived Cmax exceeds single-dose Cmax by a factor of 1.04, and AUCτ by a factor of 1.38. Minimal residual concentrations of nintedanib remain stable for more than one year.

Transport

Nintedanib is a substrate of P-glycoprotein (P-gp). See section "Interaction with other medicinal products and other forms of interaction" for information on potential interaction of nintedanib with this transporter. In vitro, nintedanib has been shown not to be a substrate or inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2. Nintedanib is also not a substrate of BCRP. In vitro, nintedanib has been shown to have weak inhibitory activity towards OCT-1, BCRP, and P-gp, which is considered to have minimal clinical significance. The same conclusion applies to nintedanib as a substrate of OCT-1.

Pharmacokinetics in special patient populations

Pharmacokinetic properties of nintedanib were comparable in healthy volunteers, patients with IPF, patients with other progressive fibrosing interstitial lung diseases, patients with SSc-ILD, and patients with oncological diseases. Based on population pharmacokinetic analysis in patients with IPF and non-small cell lung cancer (NSCLC) (N = 1,191) and descriptive studies, factors such as patient sex (adjusted for body weight), mild to moderate renal impairment (based on creatinine clearance), alcohol consumption, or P-glycoprotein genotype did not influence the effect of nintedanib. Population pharmacokinetic analysis revealed a moderate influence of sex, body weight, and race on nintedanib exposure, as described below. Due to high inter-individual variability in exposure, these minor effects were not considered clinically significant (see section "Special warnings and precautions for use").

Age

Nintedanib exposure increases linearly with age. In 45-year-old patients, AUCτ,ss was 16% lower, and in 76-year-old patients, 13% higher compared to patients with a median age of 62 years. The age range evaluated in the analysis was 29–85 years; age over 75 years was observed in approximately 5% of the patient population. Based on the population pharmacokinetic analysis model, patients aged 75 years and older showed an increase in nintedanib exposure of approximately 20–25% compared to patients under 65 years of age.

Similar studies in children have not been conducted.

Body weight

An inverse correlation between body weight and nintedanib exposure is observed. In patients with a body weight of 50 kg (5th percentile), AUCτ,ss increased by 25%, and in patients with a body weight of 100 kg (95th percentile), decreased by 19% compared to patients with a median body weight of 71.5 kg.

Race

Average nintedanib exposure is 33–50% higher in Chinese, Taiwanese, and Indian patients, 16% higher in Japanese patients, and 16–22% lower in Korean patients compared to Caucasian patients (adjusted for body weight). Data for patients of African descent are very limited; the range of these data is similar to that in Caucasian patients.

Hepatic impairment

In a dedicated Phase I study in volunteers with mild hepatic impairment (Child-Pugh class A), exposure based on Cmax and AUC was 2.2 times higher than in healthy volunteers (90% CI 1.3–3.7 for Cmax and 90% CI 1.2–3.8 for AUC, respectively). In volunteers with moderate hepatic impairment (Child-Pugh class B), exposure was 7.6 times higher based on Cmax (90% CI 4.4–13.2) and 8.7 times higher based on AUC (90% CI 5.7–13.1) compared to healthy volunteers. A study in patients with severe hepatic impairment (Child-Pugh class C) has not been conducted.

Concomitant therapy with pirfenidone

In a dedicated pharmacokinetic study, concomitant administration of nintedanib and pirfenidone was investigated in patients with IPF (idiopathic pulmonary fibrosis). Group 1 received a single dose of 150 mg nintedanib before and after increasing pirfenidone dose to 801 mg three times daily at steady state (N = 20 treated patients). Group 2 received steady-state treatment with 801 mg pirfenidone three times daily and participated in PK parameter determination before and after 7 days of concomitant treatment with nintedanib 150 mg twice daily (N = 17 treated patients). In Group 1, adjusted geometric mean ratio [90% confidence interval (CI)] values for Cmax and AUC0-tz of nintedanib were 93% (57–151%) and 96% (70–131%), respectively (n = 12 for within-subject comparison). In Group 2, adjusted geometric mean ratio (90% CI) values were 97% (86–110%) and 95% (86–106%) for Cmax,ss and AUCτ,ss of pirfenidone, respectively (n = 12 for between-subject comparison).

This study did not reveal any evidence of significant pharmacokinetic drug interaction between nintedanib and pirfenidone when used in combination (see section "Special warnings and precautions for use").

Concomitant treatment with bosentan

In a dedicated pharmacokinetic study, concomitant administration of OFEV with bosentan was investigated in healthy volunteers. Subjects received a single dose of OFEV 150 mg before and after multiple doses of bosentan 125 mg twice daily under inpatient conditions. Adjusted geometric mean ratios (90% confidence interval (CI)) were 103% (86–124%) and 99% (91–107%) for Cmax and AUC0-tz of nintedanib, respectively (n=13), indicating that concomitant administration of nintedanib with bosentan does not alter the pharmacokinetics of nintedanib.

Concomitant use of 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 taking 150 mg nintedanib twice daily for at least 10 days. 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 concomitant administration of nintedanib does not have a significant effect on plasma levels of ethinylestradiol and levonorgestrel.

Exposure–response coefficient

Exposure–response analyses in patients with IPF and other chronic fibrosing interstitial lung diseases with progressive phenotype revealed a weak relationship between plasma levels of nintedanib and increases in ALT and/or AST. The actual administered dose may be a better predictor of the risk of diarrhea of any intensity, although plasma levels of nintedanib cannot be excluded as a risk-determining factor (see section "Special warnings and precautions for use").

Clinical characteristics.

Indications.

OFEV is indicated for the treatment of idiopathic pulmonary fibrosis (IPF) in adults.

OFEV is also indicated for the treatment of other chronic fibrosing interstitial lung diseases (ILD) with a progressive phenotype in adults (see section "Pharmacological properties. Pharmacodynamics").

OFEV is indicated for the treatment of interstitial lung disease associated with systemic sclerosis (systemic scleroderma) (SSc-ILD).

Contraindications.

Pregnancy (see section "Use during pregnancy or breastfeeding").

Hypersensitivity to nintedanib, peanuts, soy, or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other types of interactions.

P-glycoprotein (P-gp)

Nintedanib is a substrate of P-gp (see section "Pharmacological properties. Pharmacokinetics"). A dedicated drug interaction study showed that co-administration with the potent P-gp inhibitor ketoconazole increases nintedanib exposure by a factor of 1.61 for AUC and by a factor of 1.83 for Cmax. A dedicated drug interaction study demonstrated that concomitant administration of rifampicin (a potent P-gp inducer) reduces nintedanib exposure by 50.3% for AUC and by 60.3% for Cmax (compared to nintedanib alone). Potent P-gp inhibitors (e.g., ketoconazole, erythromycin, or cyclosporine) may increase nintedanib exposure when co-administered with OFEV. Therefore, nintedanib tolerability should be carefully monitored in patients. If adverse reactions occur, temporary interruption of therapy, dose reduction, or discontinuation of OFEV treatment may be required (see section "Method of administration and dosage").

Potent P-gp inducers (e.g., rifampicin, carbamazepine, phenytoin, and St. John's wort preparations) may reduce nintedanib exposure. It is recommended to consider alternative concomitant therapies with no or minimal P-gp inducing effects.

Cytochrome (CYP) isoenzymes

CYP isoenzymes play only a minor role in the biotransformation of nintedanib. In preclinical studies, nintedanib and its metabolites (BIBF 1202 – the free acid metabolite of nintedanib and its glucuronide BIBF 1202 glucuronide) did not inhibit or induce CYP isoenzymes (see section "Pharmacological properties. Pharmacokinetics"). Therefore, the likelihood of drug interactions involving nintedanib based on CYP metabolism is considered low.

Concomitant use with other medicinal products

Concomitant administration of nintedanib with oral hormonal contraceptives did not significantly alter the pharmacokinetics of oral contraceptives (see section "Pharmacological properties. Pharmacokinetics").

Concomitant administration of nintedanib with bosentan does not alter the pharmacokinetics of nintedanib (see section "Pharmacological properties. Pharmacokinetics").

Special precautions for use.

Gastrointestinal disorders

Diarrhea

In clinical studies (see section "Pharmacological properties. Pharmacodynamics"), diarrhea was the most common gastrointestinal adverse reaction (see section "Adverse reactions"). In most patients, these adverse events were of mild to moderate severity and occurred during the first 3 months of treatment.

During the post-marketing period, serious cases of diarrhea leading to dehydration and electrolyte disturbances have been reported. Treatment of diarrhea (adequate hydration and anti-diarrheal medications, e.g., loperamide) should be initiated at the first signs of diarrhea. Dose reduction or interruption of treatment may be required if diarrhea develops. Treatment with OFEV may be resumed at a reduced dose (100 mg twice daily) or the full dose (150 mg twice daily). If severe diarrhea persists despite symptomatic treatment, therapy with OFEV should be discontinued.

Nausea and vomiting

Nausea and vomiting were commonly reported gastrointestinal adverse events (see section "Adverse reactions"). In most patients, nausea and vomiting were of mild to moderate severity. In the study, the frequency of nausea and vomiting leading to discontinuation of OFEV therapy was 2.1% and 1.4%, respectively.

If symptoms persist despite appropriate symptomatic therapy (including antiemetic agents), dose reduction or temporary interruption of treatment may be necessary. Treatment may be resumed at a reduced dose (100 mg twice daily) or the full dose (150 mg twice daily). If severe symptoms persist, therapy with OFEV should be discontinued.

Liver function disorders

The safety and efficacy of OFEV in patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment have not been studied. Therefore, treatment of such patients with OFEV is not recommended (see section "Dosage and administration"). Due to the enhanced effect of the drug, the risk of adverse reactions may be increased in patients with mild hepatic impairment (Child-Pugh class A). Patients with mild hepatic impairment (Child-Pugh class A) should be treated with a reduced dose of OFEV (see sections "Dosage and administration" and "Pharmacological properties. Pharmacokinetics").

Cases of drug-induced liver injury, including severe liver injury with fatal outcome, have been observed during nintedanib treatment. Most liver-related events occur within the first three months of treatment. Therefore, liver transaminase and bilirubin levels should be measured before starting treatment with OFEV and during the first month of treatment. Thereafter, these parameters should be monitored regularly during the following two months of treatment and periodically thereafter, e.g., during each patient visit or as clinically indicated.

In most cases, elevations in liver enzymes [ALT, AST, alkaline phosphatase, gamma-glutamyl transferase (GGT); see section "Adverse reactions"] and bilirubin were reversible after dose reduction or treatment interruption.

If transaminase levels (AST or ALT) increase more than 3 times the upper limit of normal, it is recommended to reduce the dose or interrupt treatment with OFEV and closely monitor the patient. Once transaminase levels return to baseline, treatment with OFEV may be resumed at the full dose (150 mg twice daily) or at a reduced dose (100 mg twice daily), which may later be increased to the full dose (see section "Dosage and administration"). If elevated liver function parameters are associated with clinical signs of liver injury, such as jaundice, treatment with OFEV should be permanently discontinued. Alternative causes of elevated liver enzymes should be investigated.

Patients with low body weight (≤65 kg), of Asian origin, and female patients are at increased risk of elevated liver enzymes. Nintedanib exposure increases linearly with age, which also increases the risk of elevated liver enzymes (see section "Pharmacological properties. Pharmacokinetics"). Close monitoring is recommended for patients with these risk factors.

Kidney function

Cases of impaired renal function/renal failure, some of which were fatal, have been observed during nintedanib treatment (see section "Adverse reactions").

Patients should be monitored during nintedanib therapy, especially those with risk factors for impaired renal function/renal failure. Dose adjustment should be considered in case of impaired renal function/renal failure (see section "Dosage and administration. Dose adjustment").

Bleeding

Inhibition of the vascular endothelial growth factor receptor (VEGFR) may be associated with an increased risk of bleeding.

Patients with known risk of bleeding, including those with hereditary predisposition to bleeding or those receiving high-dose anticoagulant therapy, were not included in clinical studies. During the post-marketing period, mild and severe bleeding events, some of which were fatal, have been reported (including in patients receiving anticoagulant therapy or other drugs that may cause bleeding, as well as in patients not receiving anticoagulant therapy). Therefore, treatment with OFEV should be prescribed to these patients only if the expected benefit outweighs the potential risk.

Arterial thromboembolism

Patients with recent myocardial infarction or stroke were not included in clinical studies. Arterial thromboembolic events were infrequent in the studies (2.5% in the OFEV group vs. 0.7% in the placebo group in the INPULSIS study; 0.9% in the OFEV group vs. 0.9% in the placebo group in the INBUILD study; 0.7% in the OFEV group vs. 0.7% in the placebo group in the SENSCIS study). In the INPULSIS studies, myocardial infarction occurred more frequently in the OFEV group (1.6%) compared to the placebo group (0.5%), whereas adverse reactions reflecting ischemic heart disease were comparable between the OFEV and placebo groups. In the INBUILD study, myocardial infarction was infrequent: 0.9% in the OFEV group vs. 0.9% in the placebo group. In the SENSCIS study, arterial thromboembolic events were rare: 0.7% in the placebo group and 0.7% in the OFEV group. Myocardial infarction was infrequent in the placebo group (0.7%) and not observed in the OFEV group. Caution should be exercised when treating patients with high cardiovascular risk, including known coronary artery disease. Consideration should be given to interrupting treatment in patients who develop symptoms of acute myocardial ischemia.

Aneurysms and arterial dissections

The use of vascular endothelial growth factor (VEGF) inhibitors in patients with or without hypertension may lead to the development of aneurysms and/or arterial dissections. The risk should be carefully evaluated before initiating OFEV in patients with risk factors such as hypertension or a history of aneurysm.

Vein thromboembolism

No increased risk of venous thromboembolic complications was observed in patients receiving nintedanib in clinical studies. However, due to the mechanism of action of nintedanib, an increased risk of thromboembolic events cannot be excluded.

Gastrointestinal (GI) perforations and ischemic colitis

The incidence of perforation was 0.3% in both treatment groups in clinical studies. However, due to the mechanism of action of nintedanib, the risk of GI perforations may be increased. During the post-marketing period, cases of gastrointestinal perforation and ischemic colitis, some of which were fatal, have been reported. Particular attention should be paid to treating patients with a history of abdominal surgery, peptic ulcer, diverticular disease, or concomitant use of corticosteroids or NSAIDs. Therefore, OFEV should be administered no sooner than 4 weeks after abdominal surgery. If GI perforation or ischemic colitis occurs, treatment with OFEV should be discontinued. In exceptional cases, OFEV may be restarted after complete recovery from ischemic colitis and careful assessment of the patient's condition and other risk factors.

Nephrotic proteinuria and thrombotic microangiopathy

Very rare cases of nephrotic proteinuria with or without impaired renal function have been reported during the post-marketing period. Histological findings in individual cases were consistent with glomerular microangiopathy with or without thrombi in the kidneys. Symptoms resolved after discontinuation of OFEV, although residual proteinuria was observed in some cases. Discontinuation of treatment should be considered in patients with signs or symptoms of nephrotic syndrome.

The use of VEGF inhibitors has been associated with thrombotic microangiopathy, including a very small number of reports with nintedanib. If laboratory or clinical findings suggest thrombotic microangiopathy in patients receiving nintedanib, treatment with nintedanib should be discontinued and a thorough evaluation of thrombotic microangiopathy should be performed.

Arterial hypertension

OFEV may increase blood pressure; therefore, blood pressure should be monitored periodically and as clinically indicated.

Pulmonary hypertension

Data on the use of OFEV in patients with pulmonary hypertension are limited.

Patients with significant pulmonary hypertension (cardiac index ≤2 L/min/m², parenteral epoprostenol/treprostinil, or significant right ventricular failure) were excluded from the INBUILD and SENSCIS studies. Close monitoring of patients with pulmonary hypertension is recommended.

Impaired wound healing

An increased frequency of impaired wound healing was not observed in clinical studies. However, due to the mechanism of action of nintedanib, this substance may negatively affect wound healing. No specific studies on the effect of nintedanib on wound healing have been conducted. Therefore, treatment with OFEV should be initiated or resumed (if interrupted due to surgery) based on clinical judgment regarding adequate wound healing.

Treatment of patients with very rare progressive ILDs

The INBUILD study was not designed or powered to provide evidence of benefit of nintedanib in subgroups with ILD diagnoses. Consistent effects were demonstrated across ILD diagnostic subgroups (see section "Pharmacodynamics"). Experience with nintedanib in very rare progressive fibrosing ILDs is limited. Clinical criteria for progression used in the INBUILD study are described in the section "Pharmacodynamics".

Concomitant therapy with pirfenidone

A dedicated pharmacokinetic study evaluated concomitant treatment with nintedanib and pirfenidone in patients with IPF (idiopathic pulmonary fibrosis). This study did not reveal any evidence of significant pharmacokinetic drug interaction between nintedanib and pirfenidone when used in combination (see section "Pharmacological properties. Pharmacokinetics"). Due to the similar safety profiles of both drugs, additive adverse reactions, including gastrointestinal and hepatic events, may be expected. The benefit-risk ratio of concomitant treatment with pirfenidone has not been established.

Effect on QT interval

No signs of QT interval prolongation were observed with nintedanib in the clinical study program (see section "Pharmacological properties. Pharmacodynamics"). Since some other tyrosine kinase inhibitors are known to affect QT, nintedanib should be used with caution in patients at risk of QT prolongation.

Allergic reactions

Products containing soy are known to cause allergic reactions, including severe anaphylactic shock, in individuals with soy allergy. Patients with known peanut allergy are at risk of severe reactions to products containing soy. One 100 mg capsule contains 1.2 mg of soy lecithin; one 150 mg capsule contains 1.8 mg of soy lecithin.

Use during pregnancy or breastfeeding.

Women of reproductive potential

Nintedanib may have adverse effects on the human fetus. Women of reproductive potential should use effective contraception to avoid pregnancy during treatment with OFEV and for at least 3 months after the last dose of OFEV. Nintedanib does not significantly affect plasma levels of ethinylestradiol and levonorgestrel (see section "Pharmacological properties. Pharmacokinetics"). The effectiveness of oral hormonal contraceptives may be reduced in the presence of vomiting and/or diarrhea or other conditions affecting absorption. Women taking oral hormonal contraceptives and experiencing such conditions should be advised to use alternative highly effective contraceptive methods.

Pregnancy

No specific studies on the use of OFEV in pregnant women have been conducted. However, reproductive toxicity of this active substance has been demonstrated in preclinical animal studies. Since nintedanib may have embryotoxic effects in humans, it should not be used during pregnancy (see section "Contraindications"). A pregnancy test should be performed before starting treatment with OFEV and during treatment as appropriate.

Patients should inform their physician immediately if they become pregnant during treatment with OFEV.

If pregnancy occurs during treatment with OFEV, therapy should be discontinued and the patient should be informed about the potential embryotoxic risk of the drug.

Breastfeeding

There are no data on the excretion of nintedanib and its metabolites into human breast milk. Preclinical studies have shown that a small amount of nintedanib and its metabolites (≤0.5% of the administered dose) passes into breast milk in animals during lactation. Therefore, risk to newborns and infants cannot be excluded. Breastfeeding should be discontinued during treatment with OFEV.

Fertility

No evidence of fertility impairment in males was observed in preclinical studies. In subacute and chronic toxicity studies, where systemic exposure to the drug was comparable to that achieved with the maximum recommended human dose (150 mg twice daily), no evidence of fertility impairment was observed in female animals.

Ability to affect reaction speed when driving or operating machinery.

OFEV has a minor influence on the ability to drive or operate machinery. Patients should be advised to exercise caution when driving or operating machinery during treatment with OFEV.

Administration and Dosage

Treatment with the medicinal product should be initiated by a physician experienced in managing patients with diseases for which OFEV is approved.

Dosage

The recommended dose of the medicinal product is 150 mg twice daily, approximately 12 hours apart. A dose of 100 mg twice daily is recommended only for patients who do not tolerate the 150 mg dose twice daily.

If any dose of the medicinal product is missed, the patient should continue taking the medication at the next scheduled dose according to the prescribed regimen. The patient should not take an additional dose if a dose has been missed. The maximum daily dose is 300 mg.

Dosage Adjustment

In the event of adverse reactions to OFEV (see sections "Special Warnings", "Adverse Reactions"), in addition to symptomatic therapy, if necessary, dose reduction or temporary interruption of treatment is recommended until the adverse reaction decreases to a level that allows resumption of therapy. Treatment with OFEV may be resumed at the full dose (150 mg twice daily) or at a reduced dose (100 mg twice daily). If the patient does not tolerate the dose of 100 mg twice daily, treatment with OFEV should be discontinued.

If diarrhea, nausea, and/or vomiting persist despite appropriate supportive therapy (including antiemetic treatment), dose reduction or discontinuation of treatment may be required. Treatment with OFEV may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persistent severe diarrhea despite symptomatic treatment, therapy with OFEV should be discontinued (see section "Special Warnings").

In case of an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels more than 3 times above the upper limit of normal, treatment with OFEV should be interrupted. Once the parameters return to normal values, treatment with OFEV may be resumed at a reduced dose (100 mg twice daily), which may subsequently be increased to the full dose (150 mg twice daily) (see sections "Special Warnings", "Adverse Reactions").

Special Patient Groups

Geriatric patients (≥ 65 years)

No general differences in safety and efficacy have been observed with the use of the medicinal product in elderly patients. Dose adjustment based on patient age is not required. Patients aged 75 years and older may require dose reduction to minimize adverse events (see section "Pharmacological Properties. Pharmacokinetics").

Renal Impairment

No initial dose adjustment is required for patients with mild or moderate renal impairment. Safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Hepatic Impairment

For patients with mild hepatic impairment (Child-Pugh class A), the recommended dose of OFEV is 100 mg twice daily with approximately 12-hour intervals. For these patients, interruption or discontinuation of treatment should be considered to monitor for adverse reactions. Safety and efficacy of nintedanib have not been studied in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment. Therefore, treatment of patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment with OFEV is not recommended (see section "Pharmacological Properties. Pharmacokinetics").

Pediatric Population

Safety and efficacy of OFEV in children (under 18 years of age) have not been established. Data are lacking.

Administration

OFEV is intended for oral use. Capsules should be taken with food, swallowed whole with water; they should not be chewed. Do not open or crush the capsule. In case of contact with the capsule contents, wash hands immediately with plenty of water.

Children

The medicinal product is not used in pediatric practice.

Overdose

Symptoms

Cases of overdose have been reported in two patients participating in an oncology program who received the medicinal product at the maximum dose of 600 mg for eight days. The adverse events observed were consistent with the known safety profile of nintedanib: increased liver enzyme activity and gastrointestinal disorders. Both patients fully recovered from the adverse events. One case of unintentional overdose up to 600 mg daily for 21 days was reported in the INPULSIS trials. During the period of incorrect dosing, one mild adverse event (nasopharyngitis) occurred and resolved during this period without any other adverse reactions being recorded.

Treatment

There is no specific antidote. In case of overdose, the medicinal product should be discontinued and symptomatic therapy should be administered.

Adverse reactions

In clinical trials and the post-marketing period, the most common adverse reactions associated with the use of nintedanib were diarrhea, nausea and vomiting, abdominal pain, decreased appetite, weight loss, and increased liver enzymes.

For information on the management of certain adverse events, see section "Special precautions for use".

Table 11 lists adverse reactions by MedDRA system organ classes and frequency of occurrence, using the following frequency criteria:

very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Table 11

Description of selected adverse reactions

Diarrhea

In clinical trials (see section "Pharmacological properties. Pharmacodynamics"), diarrhea was the most common adverse event affecting the gastrointestinal tract. In most patients, adverse events were of mild to moderate severity. Diarrhea occurred within the first 3 months of treatment in more than two-thirds of patients.

In most patients, adverse events were managed successfully by means of anti-diarrheal therapy, dose reduction, or discontinuation of treatment (see section "Special precautions for use"). An overview of diarrhea cases in clinical trials is presented in Table 12.

Table 12

Diarrhea cases in clinical trials over 52 weeks

Elevation of liver enzyme levels

In the INPULSIS trials, elevation of liver enzyme levels (see section "Special precautions") was observed in 13.6% of patients receiving nintedanib (OFEV) compared to 2.6% of patients receiving placebo. In the INBUILD trial, elevation of liver enzymes occurred in 22.6% of patients receiving OFEV compared to 5.7% receiving placebo. In the SENSCIS trial, elevation of liver enzyme levels was observed in 13.2% of patients receiving OFEV compared to 3.1% of patients receiving placebo. Elevations in liver enzyme levels were reversible and not associated with clinically evident liver disease. Additional information regarding special patient populations, recommended actions, and dose adjustments in the event of diarrhea and elevated liver enzymes is provided in the sections "Special precautions" and "Dosage and administration".

Hemorrhage

In clinical trials, the incidence of hemorrhage was slightly higher or comparable in the OFEV treatment group compared to the placebo group (10.3% in the OFEV group versus 7.8% in the placebo group in the INPULSIS trial; 11.1% in the OFEV group versus 12.7% in the placebo group in the INBUILD trial; 11.1% in the OFEV group versus 8.3% in the placebo group in the SENSCIS trial). Mild epistaxis was the most frequently reported hemorrhagic adverse event. Serious hemorrhagic events were infrequent in both groups (1.3% in the OFEV group versus 1.4% in the placebo group in the INPULSIS trial; 0.9% in the OFEV group versus 1.5% in the placebo group in the INBUILD trial; 1.4% in the OFEV group versus 0.7% in the placebo group in the SENSCIS trial).

Post-marketing cases of hemorrhage have been reported involving the gastrointestinal, respiratory, and central nervous systems, but are not limited to these. The highest frequency of hemorrhage was associated with the gastrointestinal system (see section "Special precautions").

Proteinuria

In clinical trials, the frequency of patients with proteinuria was low and comparable between treatment groups (0.8% in the OFEV group versus 0.5% in the placebo group in the INPULSIS trial; 1.5% in the OFEV group versus 1.8% in the placebo group in the INBUILD trial; 1.0% in the OFEV group versus 0.0% in the placebo group in the SENSCIS trial). Nephrotic syndrome was not reported during clinical trials.

During the post-marketing period, very rare cases of nephrotic-range proteinuria, with or without impaired renal function, have been reported. Histological findings in individual cases were consistent with glomerular microangiopathy, with or without renal thrombi. Resolution of symptoms was observed after discontinuation of OFEV, although in some cases residual proteinuria persisted. Discontinuation of treatment should be considered in patients who develop signs or symptoms suggestive of nephrotic syndrome (see section "Special precautions").

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

10 capsules in a blister made of aluminum foil with perforation, 6 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Boehringer Ingelheim Pharma GmbH & Co. KG.

Manufacturer's address and location of operations.

Binger Strasse 173, 55216, Ingelheim am Rhein, Germany.