Vargatef

Nintedanib.

VARGATEF 100 mg Soft Capsules: 1 capsule contains 100 mg of nintedanib (=free base) corresponding to 120.4 mg 1H-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl] amino]phenyl] amino]phenylmethylene]-2-oxo-, methyl ester, (3Z)-, ethanesulfonate (1:1) (=nintedanib esilate).
VARGATEF 150 mg Soft Capsules: 1 capsule contains 150 mg of nintedanib (= free base) corresponding to 180.6 mg 1H-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl] amino]phenyl]amino]phenylmethylene]-2-oxo-, methyl ester, (3Z)-, ethanesulfonate (1:1) (=nintedanib esilate.)
Excipients/Inactive Ingredients: Capsule fill: Medium chain triglycerides, hard fat, soya lecithin (E322).
Capsule shell: 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).

Pharmacotherapeutic Group: Antineoplastic agents - Protein-tyrosine kinase inhibitors. ATC Code: L01XE31.
Pharmacology: Pharmacodynamics: Mechanism of Action: Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and ß) 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.
Pharmacodynamics Effects: 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.
Clinical Trials: Efficacy in the Pivotal Phase 3 trial LUME-Lung 1: The efficacy and safety of VARGATEF 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 as follows, 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). (See Figure.)

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An pre specified evaluation was performed in the population of adenocarcinoma patients considered to have entered the study with a particularly poor treatment prognosis, namely, patients who progressed during or shortly after 1^st line therapy prior to study entry. This population included those adenocarcinoma patients identified at baseline as having progressed and entered the study less than 9 months since start of their first-line therapy. Treatment of these patients with nintedanib 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.
Quality of Life: 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.
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 C_max and 1.38-fold for AUC_τ. Nintedanib trough concentrations remained stable for more than one year.
Absorption: Nintedanib reached maximum plasma concentrations approximately 2-4 hours after oral administration as soft gelatin capsule under fed conditions (range 0.5-8 hours). The absolute bioavailability of a 100 mg dose was 4.69% (90% CI: 3.615-6.078) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.
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 t_max 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 (V_ss: 1050 L, 45.0% gCV) was observed.
The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.869.
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.
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: 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.
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 the following intrinsic and extrinsic factors. Based on the high inter-individual variability of exposure observed in the clinical trials these effects are not considered clinically relevant. (See Precautions.)
Age: Exposure to nintedanib increased linearly with age. AUC_τ,ss decreased by 16% for a 45-year old patient (5^th percentile) and increased by 13% for a 76-year old patient (95^th percentile) relative to a patient with the median age of 62 years. The age range covered by the analysis was 29 to 85 years; approximately 5% of the population was older than 75 years.
Studies in paediatric populations have not been performed.
Body Weight: An inverse correlation between body weight and exposure to nintedanib was observed. AUC_τ,ss increased by 25% for a 50 kg patient (5^th percentile) and decreased by 19% for a 100 kg patient (95^th percentile) relative to a patient with the median weight of 71.5 kg.
Race: The geometric mean exposure to nintedanib was 33-50% higher in Chinese, Taiwanese, and Indian patients and 16% higher in Japanese patients while it was 16-22% lower in Koreans compared to Caucasians (body weight corrected).
Data from Black individuals was very limited but in the same range as for Caucasians.
Hepatic Impairment: In a dedicated single dose phase I study and compared to healthy subjects, exposure to nintedanib based on C_max and AUC was 2.2-fold higher in volunteers with mild hepatic impairment (Child Pugh A; 90% of CI 1.3-3.7 for C_max and 1.2-3.8 for AUC, respectively). In volunteers with moderate hepatic impairment (Child Pugh B), exposure was 7.6-fold higher based on C_max (90% CI 4.4-13.2) and 8.7-fold higher (90% CI 5.7-13.1) based on AUC, respectively, compared to healthy volunteers. Subjects with severe hepatic impairment (Child Pugh C) have not been studied.
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: 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.

VARGATEF 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.

Treatment with VARGATEF 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 VARGATEF is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21-day docetaxel treatment cycle.
VARGATEF must not be taken on the same day of docetaxel chemotherapy administration (= day 1).
VARGATEF 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.
The recommended maximum daily dose of 400 mg should not be exceeded.
Patients may continue therapy with VARGATEF after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs.
Dose adjustments: As initial measure for the management of adverse reactions (see Tables 2 and 3) treatment with VARGATEF should be temporarily interrupted until the specific adverse reaction has resolved to levels that allow continuation of therapy (to grade 1 or baseline). VARGATEF 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 2 and Table 3.
In case of further persistence of the adverse reaction(s), i.e. if a patient does not tolerate 100 mg twice daily, treatment with VARGATEF should be permanently discontinued.
In case of specific elevations of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) values to >3 x upper limit normal (ULN) in conjunction with an increase of total bilirubin to ≥2 x ULN and alkaline phosphatase ALKP <2 x ULN (see Table 3) treatment with VARGATEF should be interrupted. Unless there is an alternative cause established, VARGATEF should be permanently discontinued. (See Precautions and Tables 2 and 3.)

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Special Populations: Paediatric Population: The safety and efficacy of VARGATEF 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 VARGATEF are necessary (see Precautions and Pharmacology: Pharmacokinetics under Actions). Safety data for Black patients are limited.
Body Weight: Based on population PK analyses, no a priori dose adjustments of VARGATEF 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).
No adjustment of the starting dose is needed for patients with mild hepatic impairment based on clinical data (Child Pugh A, see Precautions).
The safety and efficacy is 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 VARGATEF is not recommended see Pharmacology: Pharmacokinetics under Actions.

There is no specific antidote or treatment for VARGATEF 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.

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

Gastrointestinal Disorders: Diarrhoea: Diarrhoea was the most frequently reported gastro-intestinal event and appeared in close temporal relationship with the administration of docetaxel (see Side Effects). In the clinical trial LUME-Lung 1 (see Pharmacology: Pharmacodynamics 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 VARGATEF (see Dosage & Administration).
Nausea and Vomiting: Nausea and vomiting, mostly of mild to moderate severity, were frequently reported gastrointestinal adverse events (see Side Effects). If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction, treatment interruption or discontinuation of therapy with VARGATEF (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.
Neutropenia and Sepsis: A higher frequency of neutropenia of CTCAE grade >3 was observed in patients treated with VARGATEF 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 VARGATEF has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore treatment with VARGATEF is not recommended in such patients.
Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A; see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cases of drug-induced liver injury have been observed with nintedanib treatment. In the post-marketing period, severe liver injury with fatal outcome has been reported.
Elevations of liver enzymes (ALT, AST, ALKP, gamma-glutamyltransferase (GGT)) and bilirubin, were reversible upon dose reduction or interruption in the majority of cases.
Transaminase, ALKP and bilirubin levels should be investigated before the initiation of the combination treatment with VARGATEF 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 VARGATEF is continued as monotherapy after discontinuation of docetaxel.
If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with VARGATEF may be required (see Table 3 in Dosage & Administration). Alternative causes of the liver enzyme elevations should be investigated and respective action should be taken as necessary.
In case of specific changes in liver values (AST/ALT >3 x ULN in conjunction with bilirubin ≥2 x ULN and ALKP <2 x ULN) treatment with VARGATEF should be interrupted. Unless there is an alternative cause established, VARGATEF should be permanently discontinued (see Table 3 in Dosage & Administration).
Female and Asian patients have a higher risk of elevations in liver enzymes.
Nintedanib exposure increased linearly with patient age, 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 patient with these risk factors.
Haemorrhage: VEGFR inhibition might be associated with an increased risk of bleeding. In the clinical trial (LUME-Lung 1) with VARGATEF, 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 VARGATEF should be carefully weighed and discontinuation of VARGATEF may be considered. If treatment with VARGATEF is resumed, a reduced daily dose is recommended (see Table 2 under Dosage & Administration).
Patients with recent pulmonary bleeding (> 2.5 mL of red blood) as well as patients with centrally located tumours with radiographic evidence of local invasion of major blood vessels or radiographic evidence of cavitary or necrotic tumours have been excluded from clinical trials. Therefore, it is not recommended to treat these patients with VARGATEF.
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 VARGATEF 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 VARGATEF.
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 VARGATEF. 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 VARGATEF 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.
Arterial thromboembolic events: 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. Use caution when treating patients with a higher cardiovascular risk including known coronary artery disease. Treatment interruption should be considered in patients who develop signs or symptoms of acute myocardial ischaemia.
Venous thromboembolism: Patients treated with VARGATEF have an increased risk of venous thromboembolism including deep vein thrombosis. Patients should be closely monitored for thromboembolic events. VARGATEF should be discontinued in patients with life-threatening venous thromboembolic reactions.
Gastrointestinal perforations: The frequency of gastrointestinal perforation was comparable between the treatment arms in the LUME-Lung 1 study.
Due to the mechanism of action nintedanib patients might have an increased risk of gastrointestinal perforations. Particular caution should be exercised when treating patients with previous abdominal surgery or a recent history of a hollow organ perforation. VARGATEF should therefore only be initiated at least 4 weeks after major, incl. abdominal, surgery. Therapy with VARGATEF 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 VARGATEF should therefore only be initiated or - in case of perioperative interruption - resumed based on clinical judgement of adequate wound healing.
Soya lecithin: VARGATEF soft capsules contain soya lecithin (see Contraindications).
Special population: 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 VARGATEF.
Impairment of Fertility: Based on preclinical investigations, there is no evidence for impairment of male fertility (see Pharmacology: Toxicology under Actions). From subchronic and chronic toxicity studies, there is no evidence that female fertility in rats is impaired at a systemic exposure level comparable with that at the maximum recommended human dose (MRHD) of 200 mg twice daily (see Pharmacology: Toxicology under Actions).
Contraception: Women of childbearing potential being treated with VARGATEF should be advised to use adequate contraception during and at least 3 months after the last dose of VARGATEF. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with VARGATEF.

Use in Pregnancy: There is no information on the use of VARGATEF 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 VARGATEF.
Female patients should be advised to notify their doctor or pharmacist if becoming pregnant during therapy with VARGATEF.
If the patient becomes pregnant while receiving VARGATEF the patient should be apprised of the potential hazard to the foetus. Termination of the treatment should be considered.
Use in 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 VARGATEF.
For fertility, pregnancy and lactation information for docetaxel please refer to the corresponding product information for docetaxel.

Summary of the Safety Profile: 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 and based on data observed during the post-marketing period. The most frequently reported adverse reactions specific for nintedanib were diarrhoea, increased liver enzyme values (ALT and AST) and vomiting. Table 4 provides a summary of the adverse reactions by System Organ Class (SOC).
For the management of selected adverse reactions please also refer to Precautions. (See Table 4.)

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P-glycoprotein (P-gp): Nintedanib is a substrate of P-gp (see Pharmacology: Pharmacokinetics under Actions). Co-administration with the potent P-gp inhibitor ketoconazole increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on C_max in a dedicated drug-drug interaction study.
In a drug-drug interaction study with the potent P-gp inducer rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on C_max upon co-administration with rifampicin compared to administration of nintedanib alone.
If co-administered with VARGATEF, 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 VARGATEF (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: VARGATEF is recommended to be taken with food (see Pharmacology: Pharmacokinetics under Actions).
Cytochrome (CYP)-enzymes: Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways. Nintedanib and its metabolites, the free acid moiety BIBF 1202 and its glucuronide BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in preclinical studies (see Pharmacology: Pharmacokinetics under Actions). The likelihood of drug-drug interactions with nintedanib based on CYP metabolism is therefore considered to be low.
Co-administration with other drugs: Co-administration of nintedanib with docetaxel (75 mg/m²) did not alter the pharmacokinetics of either drug to a relevant extent.
The potential for interactions of nintedanib with hormonal contraceptives was not explored.

Do not store above 25°C. Protect from moisture.

Targeted Cancer Therapy

L01XE31 - nintedanib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer and other indications.

S

Soft cap 100 mg 6 x 10's. 150 mg 6 x 10's.