Ofev

Ofev

nintedanib

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Boehringer Ingelheim
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Contents
Nintedanib.
Description
1 capsule contains: 100 mg of nintedanib (= free base) corresponding to 120.4 mg nintedanib esilate; or 150 mg of nintedanib (= free base) corresponding to 180.6 mg nintedanib esilate.
Excipients/Inactive Ingredients: Capsule fill: Medium chain triglycerides, hard fat, soya lecithin (E322).
Capsule shell: Gelatine, glycerol 85 %, titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172), black ink (Opacode).
Black ink: Shellac glaze, iron oxide black (E172), propylene glycol (E1520).
Action
Pharmacotherapeutic group: Antineoplastic agents - Protein-tyrosine kinase inhibitor. ATC code: L01XE31.
Pharmacology: Pharmacodynamics: Mechanism of action: For the treatment of NSCLC: Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and β) and fibroblast growth factor receptors (FGFR 1-3) kinase activity. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling which is crucial for the proliferation and survival of endothelial as well as perivascular cells (pericytes and vascular smooth muscle cells). In addition Fms-like tyrosine-protein kinase (Flt)-3, lymphocyte-specific tyrosine-protein kinase (Lck) and proto-oncogene tyrosine-protein kinase Src (Src) are inhibited.
For the treatment of IPF: 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. Nintedanib binds competitively to the ATP binding pocket of these receptors and blocks the intracellular signalling which is crucial for the proliferation, migration and transformation of fibroblasts representing essential mechanisms of the IPF pathology. In addition nintedanib inhibits Flt-3, Lck, Lyn and Src kinases.
Pharmacodynamic effects: For the treatment of NSCLC: Tumour angiogenesis is an essential feature contributing to tumour growth, progression and metastasis formation and is predominantly triggered by the release of pro-angiogenic factors secreted by the tumour cell (i.e. VEGF and bFGF) to attract host endothelial as well as perivascular cells to facilitate oxygen and nutrient supply through the host vascular system. In preclinical disease models nintedanib, as single agent, effectively interfered with the formation and maintenance of the tumour vascular system resulting in tumour growth inhibition and tumour stasis. In particular, treatment of tumour xenografts with nintedanib led to a rapid reduction in tumour micro vessel density, pericytes vessel coverage and tumour perfusion.
Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) measurements showed an anti-angiogenic effect of nintedanib in humans. It was not clearly dose dependent, but most responses were seen at doses of ≥ 200 mg. Logistic regression revealed a statistically significant association of the anti-angiogenic effect to nintedanib exposure. DCE-MRI effects were seen 24-48 h after the first intake of the medicinal product and were preserved or even increased after continuous treatment over several weeks. No correlation of the DCE-MRI response and subsequent clinically significant reduction in target lesion size was found, but DCE-MRI response was associated with disease stabilization.
For the treatment of IPF: Activation of FGFR and PDGFR signalling cascades is critically involved in proliferation and migration of lung fibroblasts/myofibroblasts, the hallmark cells in the pathology of idiopathic pulmonary fibrosis. The potential impact of VEGFR inhibition on IPF pathology is currently not fully elucidated. On the molecular level, nintedanib is thought to inhibit the FGFR and PDGFR signalling cascades mediating lung fibroblast proliferation and migration by binding to the adenosine triphosphate (ATP) binding pocket of the intracellular receptor kinase domain, thus interfering with cross-activation via auto-phosphorylation of the receptor homodimers. In vitro, the target receptors are inhibited by nintedanib in low nanomolar concentrations. In human lung fibroblasts from patients with IPF nintedanib inhibited PDGF-, FGF-, and VEGF-stimulated cell proliferation with EC50 values of 11 nmol/L, 5.5 nmol/L and less than 1 nmol/L, respectively. At concentrations between 100 and 1000 nmol/L nintedanib also inhibited PDGF-, FGF-, and VEGF-stimulated fibroblast migration and TGF-β2-induced fibroblasts to myofibroblast transformation. In addition, the anti-inflammatory activity of nintedanib is thought to limit fibrotic stimulation by reduction of profibrotic mediators like IL-1β and IL-6. The contribution of the anti-angiogenic activity of nintedanib to its mechanism of action in fibrotic lung diseases is currently not clarified. In in vivo studies, nintedanib was shown to have potent anti-fibrotic and anti-inflammatory activity.
Clinical trials: For the treatment of NSCLC: Efficacy in the pivotal phase 3 trial LUME-Lung 1: The efficacy and safety of Ofev was investigated in 1314 patients with locally advanced, metastatic or recurrent NSCLC after one prior line of chemotherapy. The trial included 658 patients (50.1 %) with adenocarcinoma, 555 patients (42.2 %) with squamous cell carcinoma, and 101 patients (7.7 %) with other tumour histologies.
Patients were randomized (1:1) to receive nintedanib 200 mg orally twice daily in combination with 75 mg/m2 of i.v. docetaxel every 21 days (n = 655) or placebo orally twice daily in combination with 75 mg/m2 of docetaxel every 21 days (n = 659). Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) status (0 vs. 1), bevacizumab pretreatment (yes vs. no), brain metastasis (yes vs. no) and tumour histology (squamous vs. non-squamous tumour histology).
Patient characteristics were balanced between treatment arms within the overall population and within the adenocarcinoma patients. In the overall population 72.7 % of the patients were male. The majority of patients were non-Asian (81.6 %), the median age was 60.0 years, the baseline ECOG performance status was 0 (28.6 %) or 1 (71.3 %); one patient had a baseline ECOG performance status of 2. 5.8 % of the patients had stable brain metastasis at study entry and 3.8 % had prior bevacizumab treatment.
The disease stage was determined at the time of diagnosis using Union Internationale Contre le Cancer (UICC) / American Joint Committee on Cancer (AJCC) Edition 6 or Edition 7. In the overall population, 16.0 % of the patients had disease stage < IIIB/IV, 22.4 %, had disease stage IIIB and 61.6 % had disease stage IV. 9.2 % of the patients entered the study with locally recurrent disease stage as had been evaluated at baseline. For patients with tumour of adenocarcinoma histology, 15.8 % had disease stage < IIIB/IV, 15.2 %, had disease stage IIIB and 69.0 % had disease stage IV.
5.8 % of the adenocarcinoma patients entered the study with locally recurrent disease stage as had been evaluated at baseline. "Locally recurrent" was defined as local re-occurrence of the tumour without metastases at study entry.
The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee (IRC) based on the intent-to-treat (ITT) population and tested by histology. Overall survival (OS) was the key secondary endpoint. Other efficacy outcomes included objective response, disease control, change in tumour size and health-related quality of life.
As shown in Table 1, the addition of nintedanib to docetaxel led to a statistically significant reduction in the risk of progression or death by 21 % for the overall population (HR 0.79; 95 % CI: 0.68 - 0.92; p = 0.0019) as determined by the IRC. This result was confirmed in the follow-up PFS analysis (HR 0.85, 95 % CI: 0.75 - 0.96; p = 0.0070) which included all events collected at the time of the final OS analysis. Overall survival analysis in the overall population did not reach statistical significance (HR 0.94; 95% CI: 0.83 - 1.05).
Of note, pre-planned analyses according to histology showed statistically significant difference in OS between treatment arms in the adenocarcinoma population only.
The addition of nintedanib to docetaxel led to a statistically significant reduction in the risk of progression or death by 23 % for the adenocarcinoma population (HR 0.77; 95% CI: 0.62 - 0.96). In line with these observations, related study endpoints such as disease control and change in tumour size showed significant improvements. (See Table 1.)


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


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A pre specified evaluation was performed in the population of adenocarcinoma patients considered to have entered the study with a particularly poor treatment prognosis, namely, patients who progressed during or shortly after 1st line therapy prior to study entry. This population included those adenocarcinoma patients identified at baseline as having progressed and entered the study less than 9 months since start of their first-line therapy. Treatment of these patients with nintedanib in combination with docetaxel reduced the risk of death by 25 %, compared with placebo plus docetaxel (HR 0.75; 95 % CI: 0.60 - 0.92; p = 0.0073). Median OS improved by 3 months (nintedanib: 10.9 months; placebo: 7.9 months).
In a post-hoc analysis in adenocarcinoma patients having progressed and entered the study ≥ 9 months since start of their first-line therapy the difference did not reach statistical significance (HR for OS: 0.89, 95% CI 0.66 - 1.19).
The proportion of adenocarcinoma patients with stage < IIIB/IV at diagnosis was small and balanced across treatment arms (placebo: 54 patients (16.1 %); nintedanib: 50 patients, (15.5 %)). The HR for these patients for PFS and OS was 1.24 (95% CI: 0.68, 2.28) and 1.09 (95% CI: 0.70, 1.70), respectively. However, the sample size was small, there was no significant interaction and the CI was wide and included the HR for OS of the overall adenocarcinoma population.
For the treatment of IPF: The clinical efficacy of nintedanib has been studied in patients with IPF in two phase 3, randomised, double-blind, placebo-controlled studies with identical design (INPULSIS-1 and INPULSIS-2). Patients were randomized in a 3:2 ratio to treatment with 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 nintedanib compared to patients receiving placebo. The treatment effect was consistent in both trials. See Table 2 for individual and pooled study results. (See Table 2.)


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


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


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


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Change from baseline in SGRQ total score at week 52: St. George's Respiratory Questionnaire (SGRQ) total score measuring health related quality of life (HRQoL) was analysed at 52 weeks. In INPULSIS-2, patients receiving placebo had a larger increase from baseline SGRQ total score as compared to patients receiving nintedanib 150 mg bid. The deterioration of HRQoL was smaller in the nintedanib group; the difference between the treatment groups was statistically significant (-2.69; 95% CI: -4.95, -0.43; p=0.0197).
In INPULSIS-1, the increase from baseline in SGRQ total score at week 52 was comparable between nintedanib and placebo (difference between treatment groups: -0.05; 95% CI: -2.50, 2.40; p=0.9657). In the pooled analysis of the INPULSIS trials, the estimated mean change from baseline to week 52 in SGRQ total score was smaller in the nintedanib group (3.53) than in the placebo group (4.96), with a difference between the treatment groups of -1.43 (95% CI: -3.09, 0.23; p = 0.0923). Overall, the effect of nintedanib on health-related quality of life as measured by the SGRQ total score is modest, indicating less worsening compared to placebo.
Time to first acute IPF exacerbation: In the INPULSIS-2 trial, the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving nintedanib 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 nintedanib compared to placebo. See Table 5 for individual and pooled study results. (See Table 5.)


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


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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 a nintedanib 150 mg bid dose group.
The primary endpoint, rate of decline in FVC over 52 weeks was lower in the nintedanib arm (-0.060 L/year, N=84) than the placebo arm (-0.190 L/year, N=83). The estimated difference between the treatment groups was 0.131 L/year (95% CI 0.027, 0.235). The difference between the treatment groups reached nominal statistical significance (p = 0.0136).
The estimated mean change from baseline in SGRQ total score at 52 weeks was 5.46 for placebo, indicating worsening of the health-related quality of life and -0.66 for nintedanib, indicating stable health-related quality of life. The estimated mean difference for nintedanib compared with placebo was -6.12 (95% CI: -10.57, -1.67; p = 0.0071).
The number of patients with acute IPF exacerbations over 52 weeks was lower in the nintedanib group (2.3%, N=86) compared to placebo (13.8%, N=87). The estimated hazard ratio of nintedanib versus placebo was 0.16 (95% CI 0.04, 0.71; p = 0.0054).
Quality of Life: For the treatment of NSCLC: Treatment with nintedanib did not significantly change the time to deterioration of the pre-specified symptoms cough, dyspnoea and pain, but resulted in a significant deterioration in the diarrhoea symptom scale. Nevertheless, the overall treatment benefit of nintedanib was observed without adversely affecting self-reported quality of life.
Effect on QT interval: QT/QTc measurements were recorded and analysed from a dedicated study comparing nintedanib monotherapy against sunitinib monotherapy in patients with renal cell carcinoma. In this study single oral doses of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administered twice daily for 15 days did not prolong the QTcF interval.
For the treatment of NSCLC: However, no thorough QT-trial of nintedanib administered in combination with docetaxel was conducted.
Paediatric studies: No clinical trials have been conducted in children and adolescents.
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 Cmax and 1.38-fold for AUCτ. 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 gelatine 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.
Dose proportionality was shown by increase of nintedanib exposure (dose range 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 tmax fasted: 2.00 hours; fed: 3.98 h).
Distribution: Nintedanib follows at least bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution (Vss : 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.
Metabolism: 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.
For the treatment of NSCLC: In preclinical in vivo experiments, BIBF 1202 did not show efficacy despite its activity at target receptors of the substance.
Elimination: Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min, 28.8 % gCV). Urinary excretion of the unchanged active substance within 48 hours was about 0.05 % of dose (31.5 % gCV) after oral and about 1.4 % of the dose (24.2 % gCV) after intravenous administration; the renal clearance was 20 mL/min (32.6 % gCV). The major route of elimination of drug related radioactivity after oral administration of [14C] nintedanib was via faecal/biliary excretion (93.4 % of dose, 2.61 % gCV). The contribution of renal excretion to the total clearance was low (0.649 % of dose, 26.3 % gCV). The overall recovery was considered complete (above 90 %) within 4 days after dosing. The terminal half-life of nintedanib was between 10 and 15 h (gCV % approximately 50 %).
Exposure-response relationship: For the treatment of NSCLC: In exploratory pharmacokinetic(PK)-adverse event analyses, higher exposure to nintedanib tended to be associated with liver enzyme elevations, but not with gastrointestinal adverse events.
PK-efficacy analyses were not performed for clinical endpoints. Logistic regression revealed a statistically significant association between nintedanib exposure and DCE-MRI response.
For the treatment of IPF: Exposure-response analyses indicated an Emax-like relationship between exposure in the range observed in Phase II and III and the annual rate of decline in FVC with an EC50 of around 3-5 ng/mL (relative standard errors: 54-67%).
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, and cancer patients. Based on results of Population PK (PopPK) analyses and descriptive investigations, exposure to nintedanib was not influenced by sex (body weight corrected), mild and moderate renal impairment (estimated by creatinine clearance), liver metastases, ECOG performance score, alcohol consumption, or P-gp genotype. Population PK analyses indicated moderate effects on exposure to nintedanib depending on age, body weight, and race (see as follows). Based on the high inter-individual variability of exposure observed in the clinical LUME-Lung 1 trial these effects are not considered clinically relevant (see Precautions).
Age: Exposure to nintedanib increased linearly with age. AUCτ,ss decreased by 16 % for a 45-year old patient (5th percentile) and increased by 13 % for a 76-year old patient (95th 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.
Studies in paediatric populations have not been performed.
Body weight: An inverse correlation between body weight and exposure to nintedanib was observed. AUCτ,ss increased by 25 % for a 50 kg patient (5th percentile) and decreased by 19 % for a 100 kg patient (95th 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.
For the treatment of NSCLC: However, based on the high inter-individual variability of exposure these effects are not considered clinically relevant.
Hepatic impairment: In a dedicated single dose phase I study and compared to healthy subjects, exposure to nintedanib based on Cmax and AUC was 2.2-fold higher in volunteers with mild hepatic impairment (Child Pugh A; 90% CI 1.3 - 3.7 for Cmax 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 Cmax (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: For the treatment of IPF: Concomitant treatment of nintedanib with pirfenidone was investigated in a parallel group design study in Japanese patients with IPF. Twenty four patients were treated for 28 days with 150 mg nintedanib bid. In 13 patients, nintedanib was added to chronic treatment with standard doses of pirfenidone. Eleven patients received nintedanib monotherapy. The exposure to nintedanib tended to be lower when nintedanib was administered on top of pirfenidone compared to administration of nintedanib alone. Nintedanib had no effect on the PK of pirfenidone. Due to the short duration of concomitant exposure and low number of patients no conclusion on the safety and efficacy of the combination can be drawn.
Drug-Drug Interaction Potential: Metabolism: Drug-drug interactions between nintedanib and CYP substrates, CYP inhibitors, or CYP inducers are not expected, since nintedanib, BIBF 1202, and BIBF 1202 glucuronide did not inhibit or induce CYP enzymes preclinically nor was nintedanib metabolized by CYP enzymes to a relevant extent.
Transport: Nintedanib is a substrate of P-gp. For the interaction potential of nintedanib with this transporter, see Interactions. Nintedanib was shown to be not a substrate or inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2 or MRP-2 in vitro. Nintedanib was also not a substrate of BCRP. Only a weak inhibitory potential on OCT-1, BCRP, and P-gp was observed in vitro which is considered to be of low clinical relevance. The same applies for nintedanib being a substrate of OCT-1.
Toxicology: General toxicology: Single dose toxicity studies in rats and mice indicated a low acute toxic potential of nintedanib. In repeat dose toxicology studies in rats, adverse effects (e.g. thickening of epiphyseal plates, lesions of the incisors) were mostly related to the mechanism of action (i.e. VEGFR-2 inhibition) of nintedanib. These changes are known from other VEGFR-2 inhibitors and can be considered class effects.
Diarrhoea and vomiting accompanied by reduced food consumption and loss of body weight were observed in toxicity studies in non-rodents.
There was no evidence of liver enzyme increases in rats, dogs, and Cynomolgus monkeys.
Mild liver enzyme increases which were not due to serious adverse effects such as diarrhoea were only observed in Rhesus monkeys.
Reproduction toxicity: For the treatment of NSCLC: A study of male fertility and early embryonic development up to implantation in rats did not reveal effects on the male reproductive tract and male fertility.
In rats, embryo-foetal lethality and teratogenic effects were observed at exposure levels below human exposure at the maximum recommended human dose (MRHD) 200 mg twice daily. Effects on the development of the axial skeleton and on the development of the great arteries were also noted at subtherapeutic exposure levels.
In rabbits, embryofoetal lethality and teratogenic effects comparable to those in rats were observed at an exposure slightly higher than in rats.
In rats, small amounts of radiolabelled nintedanib and/or its metabolites were excreted into the milk (≤ 0.5 % of the administered dose).
From the 2-year carcinogenicity studies in mice and rats, there was no evidence for a carcinogenic potential of nintedanib.
Genotoxicity studies indicated no mutagenic potential for nintedanib.
For the treatment of IPF: A study of male fertility and early embryonic development up to implantation in rats did not reveal effects on the male reproductive tract and male fertility.
In rats, embryo-foetal lethality and teratogenic effects were observed at exposure levels below human exposure at the maximum recommended human dose (MRHD) of 150 mg twice daily. Effects on the development of the axial skeleton and on the development of the great arteries were also noted at subtherapeutic exposure levels.
In rabbits, embryofoetal lethality and teratogenic effects comparable to those in rats were observed at an exposure slightly higher than in rats.
In rats, small amounts of radiolabelled nintedanib and/or its metabolites were excreted into the milk (≤ 0.5 % of the administered dose.
From the 2-year carcinogenicity studies in mice and rats, there was no evidence for a carcinogenic potential of nintedanib.
Genotoxicity studies indicated no mutagenic potential for nintedanib.
Indications/Uses
Ofev is indicated in combination with docetaxel for the treatment of patients with locally advanced, metastatic or recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first line chemotherapy.
Ofev is indicated for the treatment of Idiopathic Pulmonary Fibrosis (IPF) and to slow disease progression.
Dosage/Direction for Use
Ofev capsules should be taken orally, preferably with food, swallowed whole with water, and should not be chewed or crushed.
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.
For the treatment of NSCLC: Treatment with Ofev should be initiated and supervised by a physician experienced in the use of anticancer therapies.
For posology, method of administration, and dose modifications of docetaxel, please refer to the corresponding product information for docetaxel.
The recommended dose of Ofev is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21-day docetaxel treatment cycle.
Ofev must not be taken on the same day of docetaxel chemotherapy administration (= day 1).
The recommended maximum daily dose of 400 mg should not be exceeded.
Patients may continue therapy with Ofev after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs.
For the treatment of IPF: Treatment with Ofev should be initiated by physicians experienced in the diagnosis and treatment of IPF.
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: For the treatment of NSCLC: As initial measure for the management of adverse reactions (see Tables 7 and 8) treatment with Ofev should be temporarily interrupted until the specific adverse reaction has resolved to levels that allow continuation of therapy (to grade 1 or baseline). Ofev treatment may be resumed at a reduced dose. Dose adjustments in 100 mg steps per day (i.e. a 50 mg reduction per dosing) based on individual safety and tolerability are recommended as described in Table 7 and Table 8.
In case of further persistence of the adverse reaction(s), i.e. if a patient does not tolerate 100 mg twice daily, treatment with Ofev should be discontinued.
In case of specific elevations of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) values to > 3 x upper limit normal ULN in conjunction with an increase of total bilirubin to ≥ 2 x ULN and alkaline phosphatase ALKP < 2 x ULN (see Table 8) treatment with Ofev should be interrupted. Unless there is an alternative cause established, Ofev should be permanently discontinued. (See Tables 7 and 8.)


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For the treatment of IPF: In addition to symptomatic treatment if applicable, the management of side effects (see Precautions and 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) or a reduced dose (100 mg twice daily). If a patient does not tolerate 100 mg twice daily, treatment with Ofev should be discontinued.
In case of interruptions due to transaminase (AST or ALT) elevations > 3x upper limit of normal (ULN), once transaminases have returned to baseline values, treatment with Ofev may be resumed at 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 (150 mg twice daily) (see Precautions and Adverse Reactions).
Special populations: Paediatric population: The safety and efficacy of Ofev in paediatric patients have not been studied in clinical trials.
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 on the basis of a patient's age (see Pharmacology: Pharmacokinetics under Actions).
Race: Based on population pharmacokinetic (-PK) analyses, no a priori dose adjustments of Ofev are necessary (see Precautions and Pharmacology: Pharmacokinetics: Intrinsic and Extrinsic Factors; Special Populations 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 (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: Less than 1% of a single dose of nintedanib is excreted via the kidney (see Pharmacology: Pharmacokinetics under Actions). Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (<30 ml/min CrCL).
Hepatic Impairment: Nintedanib is predominantly eliminated via biliary/faecal excretion (>90 %) Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B; see Pharmacology: Pharmacokinetics under Actions).
The safety and efficacy of nintedanib have not been investigated in patients with hepatic impairment classified as Child Pugh B and C. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Ofev is not recommended see Pharmacology: Pharmacokinetics under Actions.
For the treatment of NSCLC: No adjustment of the starting dose is needed for patients with mild hepatic impairment based on clinical data (Child Pugh A, see Precautions).
For the treatment of IPF: In 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.
Overdosage
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 case of overdose, treatment should be interrupted and general supportive measures initiated as appropriate.
For the treatment of IPF: 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.
Contraindications
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).
For the treatment of NSCLC: For contraindications of docetaxel please refer to the corresponding product information for docetaxel.
Special Precautions
Gastrointestinal-Disorders: For the treatment of NSCLC: Diarrhoea: Diarrhoea was the most frequently reported gastro-intestinal event and appeared in close temporal relationship with the administration of docetaxel (see Adverse Reactions). In the clinical trial LUME-Lung 1 (see Pharmacology: Pharmacodynamics: Clinical trials under Actions), the majority of patients had mild to moderate diarrhoea. 6.3 % of the patients had diarrhoea of grade ≥3 in combination treatment compared to 3.6 % treated with docetaxel alone. Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require interruption, dose reduction or discontinuation of therapy with Ofev (see Dosage & Administration).
Nausea and vomiting: Nausea and vomiting, mostly of mild to moderate severity, were frequently reported gastrointestinal adverse events (see Adverse Reactions). If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction, treatment interruption, or discontinuation of therapy with Ofev (see Dosage & Administration) may be required.
In the event of dehydration, administration of electrolytes and fluids is required. Plasma levels of electrolytes should be monitored, if relevant gastrointestinal adverse events occur.
For the treatment of IPF: Diarrhoea: In the INPULSIS trials (see Pharmacology: Pharmacodynamics: Clinical trials under Actions), diarrhoea was the most frequent gastro-intestinal event reported in 62.4 % versus 18.4 % of patients treated with Ofev and placebo, respectively (see Adverse Reactions). In most patients the event was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhoea led to dose reduction in 10.7% of the patients and to discontinuation of nintedanib in 4.4% of the patients.
Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require treatment interruption. Ofev treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with 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. Nausea led to discontinuation of nintedanib in 2.0% of patients. Vomiting led to discontinuation in 0.8% of the patients.
If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction or treatment interruption may be required. The treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe symptoms therapy with Ofev should be discontinued.
Diarrhoea and vomiting may lead to dehydration and/or electrolyte disturbances.
Neutropenia and Sepsis: For the treatment of NSCLC: A higher frequency of neutropenia of CTCAE grade > 3 was observed in patients treated with Ofev in combination with docetaxel as compared to treatment with docetaxel alone. Subsequent complications such as sepsis or febrile neutropenia have been observed.
Blood counts should be monitored during therapy, in particular during the combination treatment with docetaxel. Frequent monitoring of complete blood counts should be performed at the beginning of each treatment cycle and around the nadir for patients receiving treatment with nintedanib in combination with docetaxel, and as clinically indicated after the administration of the last combination cycle.
Hepatic Function: The safety and efficacy of 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.
For the treatment of NSCLC: Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A; see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cases of drug-induced liver injury have been observed with nintedanib treatment.
Administration of nintedanib was associated with an elevation of liver enzymes (ALT, AST, ALKP (alkaline phosphatase)), gamma-glutamyltransferase (GGT) and bilirubin. These increases were reversible in the majority of cases.
Female and Asian patients have a higher risk of elevations in liver enzymes.
Nintedanib exposure increased linearly with patient age and was inversely correlated to weight which may also result in a higher risk of developing liver enzyme elevations (see Pharmacology: Pharmacokinetics under Actions).
Close monitoring is recommended in patients with these risk factors.
Transaminase, ALKP and bilirubin levels should be investigated before the initiation of the combination treatment with Ofev plus docetaxel. The values should be monitored as clinically indicated or periodically during treatment, i.e. in the combination phase with docetaxel at the beginning of each treatment cycle and monthly in case Ofev is continued as monotherapy after discontinuation of docetaxel.
If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with Ofev may be required (see Dosage & Administration/Table 8). Alternative causes of the liver enzyme elevations should be investigated and respective action should be taken as necessary.
In case of specific changes in liver values (AST/ALT > 3 x ULN in conjunction with; bilirubin ≥ 2 x ULN and ALKP < 2 x ULN) treatment with Ofev should be interrupted. Unless there is an alternative cause established, Ofev should be permanently discontinued (see Dosage & Administration/Table 8).
For the treatment of IPF: Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A). 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.
Administration of nintedanib was associated with elevations of liver enzymes (ALT, AST, ALKP, gamma-glutamyl-transferase (GGT)) and bilirubin. Transaminase increases were reversible upon dose reduction or interruption. Hepatic transaminase and bilirubin levels should be investigated before the initiation of treatment with Ofev, and periodically thereafter (e.g. at each patient visit) or as clinically indicated.
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.
If transaminase (AST or ALT) elevations > 3 x 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.
Haemorrhage: For the treatment of NSCLC: VEGFR inhibition might be associated with an increased risk of bleeding. In the clinical trial (LUME-Lung 1) with Ofev, the frequency of bleeding in both treatment arms was comparable. Mild to moderate epistaxis represented the most frequent bleeding event. There were no imbalances of respiratory or fatal bleedings and no intracerebral bleeding was reported. The majority of fatal bleeding events were tumour associated.
In the post-marketing period non-serious and serious bleeding events, some of which were fatal, have been observed. In patients who experience grade 3/4 bleeding events, the benefits and risks of continuing treatment with Ofev should be carefully weighed and discontinuation of Ofev may be considered. If treatment with Ofev is resumed, a reduced daily dose is recommended (see Dosage & Administration/Table 7).
Patients with recent pulmonary bleeding (> 2.5 ml of red blood) as well as patients with centrally located tumours with radiographic evidence of local invasion of major blood vessels or radiographic evidence of cavitary or necrotic tumours have been excluded from clinical trials. Therefore it is not recommended to treat these patients with Ofev.
Brain metastasis: Stable brain metastasis: No increased frequency of cerebral bleeding in patients with adequately pre-treated brain metastases which were stable for ≥ 4 weeks before start of treatment with Ofev was observed. However, such patients should be closely monitored for signs and symptoms of cerebral bleeding.
Active brain metastasis: Patients with active brain metastasis were excluded from clinical trials and are not recommended for treatment with Ofev.
Therapeutic anticoagulation: There are no data available for patients with inherited predisposition to bleeding or for patients receiving a full dose of anticoagulative treatment prior to start of treatment with Ofev. In patients on chronic low dose therapy with low molecular weight heparins or acetylsalicylic acid, no increased frequency of bleeding was observed. Patients who developed thromboembolic events during treatment and who required anticoagulant treatment were allowed to continue Ofev and did not show an increased frequency of bleeding events. Patients taking concomitant anticoagulation, such as warfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, INR, or clinical bleeding episodes.
For the treatment of IPF: VEGFR inhibition might be associated with an increased risk of bleeding. In the INPULSIS trials with Ofev, the frequency of patients who experienced bleeding adverse events was slightly higher in the Ofev arm (10.3%) than in the placebo arm (7.8%). Non-serious epistaxis was the most frequent bleeding event. Serious bleeding events occurred with low and similar frequencies in the 2 treatment groups (placebo: 1.4%; Ofev: 1.3%).
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 the INPULSIS studies. 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: 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.
For the treatment of NSCLC: The frequency of arterial thromboembolic events was comparable between the two treatment arms in the phase 3 study 1199.13 (LUME-Lung 1). Patients with a recent history of myocardial infarction or stroke were excluded from this study. However, an increased frequency of arterial thromboembolic events was observed in patients with idiopathic pulmonary fibrosis (IPF) when treated with nintedanib monotherapy.
For the treatment of IPF: Patients with a recent history of myocardial infarction or stroke were excluded from the INPULSIS trials. Arterial thromboembolic events were infrequently reported: in 0.7% of patients in the placebo and 2.5% in the nintedanib treated group.
While adverse events reflecting ischaemic heart disease were balanced between the nintedanib and placebo groups, a higher percentage of patients experienced myocardial infarctions in the nintedanib group (1.6%) compared to the placebo group (0.5%).
Venous thromboembolism: For the treatment of NSCLC: Patients treated with Ofev have an increased risk of venous thromboembolism including deep vein thrombosis. Patients should be closely monitored for thromboembolic events. Ofev should be discontinued in patients with life-threatening venous thromboembolic reactions.
For the treatment of IPF: In the INPULSIS trials no increased risk of venous thromboembolism was observed in nintedanib treated patients. Due to the mechanism of action of nintedanib patients might have an increased risk of thromboembolic events.
Gastrointestinal perforations: Due to the mechanism of action nintedanib patients might have an increased risk of gastrointestinal perforations.
For the treatment of NSCLC: The frequency of gastrointestinal perforation was comparable between the treatment arms in the LUME-Lung 1 study. Particular caution should be exercised when treating patients with previous abdominal surgery or a recent history of a hollow organ perforation. 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.
For the treatment of IPF: In the INPULSIS trials no increased risk of gastrointestinal perforation was observed in nintedanib treated patients. Cases of gastrointestinal perforations 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.
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.
Soya lecithin: Ofev soft capsules contain soya lecithin (see Contraindications).
Special populations: For the treatment of NSCLC: In study 1199.13 (LUME-Lung 1), there was a higher frequency of serious adverse events in patients treated with nintedanib plus docetaxel with a body weight of less than 50 kg compared to patients with a weight ≥ 50 kg; however the number of patients with a body weight of less than 50 kg was small. Therefore close monitoring is recommended in patients weighing < 50 kg.
Effects on ability to drive and use 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.
Use In Pregnancy & Lactation
Fertility: For the treatment of NSCLC: Based on preclinical investigations, there is no evidence for impairment of male fertility. From subchronic and chronic toxicity studies, there is no evidence that female fertility in rats is impaired at a systemic exposure level comparable with that at the maximum recommended human dose (MRHD) of 200 mg twice daily.
For the treatment of IPF: Based on preclinical investigations, there is no evidence for impairment of male fertility. 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.
Contraception: Women of childbearing potential being treated with Ofev should be advised to use adequate contraception during and at least 3 months after the last dose of Ofev. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Ofev.
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 and pregnancy testing should be conducted at least prior to treatment with Ofev. 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 the patient should be apprised of the potential hazard to the foetus. Termination of the treatment should be considered.
Breastfeeding/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.
For the treatment of NSCLC: For fertility, pregnancy and lactation information for docetaxel please refer to the corresponding product information for docetaxel.
Adverse Reactions
Summary of the safety profile: For the management of selected adverse reactions please also refer to Precautions.
For the treatment of NSCLC: The safety data provided in the following are based on the global, double-blind randomised pivotal phase 3 trial 1199.13 (LUME-Lung 1) comparing treatment with nintedanib plus docetaxel against placebo plus docetaxel in patients with locally advanced, or metastatic, or recurrent NSCLC after first-line chemotherapy. The most frequently reported adverse reactions specific for nintedanib were diarrhoea, increased liver enzyme values (ALT and AST) and vomiting. Table 9 provides a summary of the adverse reactions by System Organ Class (SOC).
The following terms are used to rank the ADRs by frequency: 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 the available data). Within each frequency grouping adverse reactions are presented in order of decreased seriousness. (See Table 9.)


Click on icon to see table/diagram/image


Description of selected adverse reactions: Diarrhoea: Diarrhoea occurred in 43.4 % (≥ grade 3: 6.3 %) of adenocarcinoma patients in the nintedanib arm. The majority of adverse reactions appeared in close temporal relationship with the administration of docetaxel. Most patients recovered from diarrhoea following treatment interruption, anti-diarrhoeal therapy and nintedanib dose reduction.
For recommended measures and dosing adjustments in case of diarrhoea, see Precautions and Dosage & Administration, respectively.
Liver enzyme elevations and hyperbilirubinaemia: Liver-related adverse reactions occurred in 42.8 % of nintedanib-treated patients. Approximately one third of these patients had liver-related adverse reactions of ≥ grade 3 severity. In patients with increased liver parameters, the use of the established stepwise dose reduction scheme was the appropriate measure and discontinuation of treatment was only necessary in 2.2 % of patients. In the majority of patients, elevations of liver parameters were reversible.
For information about special populations, recommended measures and dosing adjustments in case of liver enzyme and bilirubin elevations, see Precautions and Dosage & Administration, respectively.
Neutropenia, febrile neutropenia and sepsis: Sepsis and febrile neutropenia have been reported as subsequent complications of neutropenia. The rates of sepsis (1.3 %) and febrile neutropenia (7.5 %) were increased under treatment with nintedanib as compared to the placebo arm. It is important that the patient's blood counts are monitored during therapy, in particular during the combination treatment with docetaxel (see Precautions).
Bleeding: In the post-marketing period non-serious and serious bleeding events, some of which fatal, have been reported, including patients with or without anticoagulant therapy or other drugs that could cause bleeding. Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous system organs, with the most frequent being respiratory (see also Precautions).
Perforation: As expected via its mechanism of action perforation might occur in patients treated with nintedanib. However, the frequency of patients with gastrointestinal perforation was low.
Peripheral neuropathy: Peripheral neuropathy is also known to occur with docetaxel treatment. Peripheral neuropathy was reported in 16.5 % of patients in the placebo arm and in 19.1 % of patients in the nintedanib arm.
For the treatment of IPF: Nintedanib has been studied in clinical trials of 1529 patients suffering from Idiopathic Pulmonary Fibrosis (IPF).
The safety data provided in the following are based on the two Phase 3, randomised, double-blind, placebo-controlled studies in 1061 patients comparing treatment with nintedanib 150 mg twice daily to placebo for 52 weeks (INPULSIS-1 and INPULSIS-2).
The most frequently reported adverse events associated with the use of nintedanib included diarrhoea, nausea and vomiting, abdominal pain, decreased appetite, weight decreased and hepatic enzyme increased.
The following terms are used to rank the ADRs by frequency: 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 the available data). Within each frequency grouping adverse reactions are presented in order of decreased seriousness. (See Table 10.)


Click on icon to see table/diagram/image


Description of selected adverse reactions: Diarrhoea: Diarrhoea was reported in 62.4% of patients treated with nintedanib. The event was reported to be of severe intensity in 3.3% of nintedanib treated patients. More than two thirds of patients experiencing diarrhoea reported its first onset already during the first three months of treatment. Diarrhoea led to permanent treatment discontinuation in 4.4% of patients; otherwise the events were managed by antidiarrhoeal therapy, dose reduction or treatment interruption (see Precautions).
Hepatic enzyme increased: Liver enzyme elevations (see Precautions) were reported in 13.6% of nintedanib treated patients. Elevations of liver enzymes were reversible and not associated with clinically manifest liver disease. For further information about special populations, recommended measures and dosing adjustments in case of diarrhoea and hepatic enzyme increased, refer additionally to Precautions and Dosage & Administration, respectively.
Inform the doctor or pharmacist immediately about side effects that occur while taking the drug.
Drug Interactions
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 Cmax 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 Cmax 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 side effects 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: The potential for interactions of nintedanib with hormonal contraceptives was not explored.
For the treatment of NSCLC: Co-administration of nintedanib with docetaxel (75 mg/m2) did not alter the pharmacokinetics of either drug to a relevant extent.
Caution For Usage
Incompatibilities: Not applicable
Storage
Store in a refrigerator (2°C - 8°C). Store in the original package in order to protect from moisture.
Shelf life: 36 months.
ATC Classification
L01XE31 - nintedanib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer and other indications.
Presentation/Packing
Softcap 100 mg (peach-colored, opaque, oblong, soft gelatin, imprinted in black on one side with Boehringer Ingelheim company symbol and with "100", and containing a bright yellow viscous suspension) x 6 x 10's. 150 mg (brown-colored, opaque, oblong, soft gelatin, imprinted in black on one side with Boehringer Ingelheim company symbol and with "150", and containing a bright yellow viscous suspension) x 6 x 10's.
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