VARGATEF 100mg capsule me medication leaflet

Vargatef 100 mg soft capsules

Vargatef 150 mg soft capsules

Vargatef 100 mg soft capsules

Each soft capsule contains 100 mg nintedanib (as esilate).

Each capsule contains 1.2 mg of soya lecithin.

Vargatef 150 mg soft capsules

Each soft capsule contains 150 mg nintedanib (as esilate).

Each capsule contains 1.8 mg of soya lecithin.

For the full list of excipients, see section 6.1.

Soft capsule (capsule).

Vargatef 100 mg soft capsules

Peach-coloured, opaque, oblong soft-gelatin capsules (approx. 16 x 6 mm) marked on one side withthe Boehringer Ingelheim company symbol and “100”.

Vargatef 150 mg soft capsules

Brown-coloured, opaque, oblong soft-gelatin capsule (approx. 18 x 7 mm) marked on one side withthe Boehringer Ingelheim company symbol and “150”.

Vargatef is indicated in combination with docetaxel for the treatment of adult patients with locallyadvanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinomatumour histology after first-line chemotherapy.

Treatment with Vargatef should be initiated and supervised by a physician experienced in the use ofanticancer therapies.

The recommended dose of nintedanib is 200 mg twice daily administered approximately 12 hoursapart, 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).

If a dose of nintedanib is missed, administration should resume at the next scheduled time at therecommended dose. The individual daily doses of nintedanib should not be increased beyond therecommended dose to make up for missed doses. The recommended maximum daily dose of 400 mgshould not be exceeded.

Patients may continue therapy with nintedanib after discontinuation of docetaxel for as long as clinicalbenefit is observed or until unacceptable toxicity occurs.

For posology, methods of administration, and dose modifications of docetaxel, please refer to thecorresponding product information for docetaxel.

As initial measure for the management of adverse reactions (see Tables 1 and 2) treatment withnintedanib should be temporarily interrupted until the specific adverse reaction has resolved to levelsthat allow continuation of therapy (to grade 1 or baseline).

Nintedanib 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 asdescribed in Table 1 and Table 2.

In case of further persistence of the adverse reaction(s), i.e. if a patient does not tolerate 100 mg twicedaily, treatment with Vargatef should be permanently discontinued. In case of specific elevations ofaspartate aminotransferase (AST)/ alanine aminotransferase (ALT) values to > 3 × upper limit normal(ULN) in conjunction with an increase of total bilirubin to ≥ 2 × ULN and alkaline phosphatase(ALKP) < 2 × ULN (see Table 2) treatment with Vargatef should be interrupted. Unless there is analternative cause established, Vargatef should be permanently discontinued (see also section 4.4).

Table 1: Recommended dose adjustments for Vargatef (nintedanib) in case of diarrhoea, vomitingand other non-haematological or haematological adverse reactions

CTCAE* Adverse reaction Dose adjustment

Diarrhoea ≥ grade 2 for more than 7 consecutivedays despite anti-diarrhoeal treatment

OR

Diarrhoea ≥ grade 3 despite anti-diarrhoeal After treatment interruption and recovery totreatment grade 1 or baseline, dose reduction from 200 mg

Vomiting ≥ grade 2 twice daily to 150 mg twice daily and - if a 2nd

AND/OR dose reduction is considered necessary - from

Nausea ≥ grade 3 150 mg twice daily to 100 mg twice daily.despite anti-emetic treatment

Other non-haematological or haematologicaladverse reaction of ≥ grade 3

* CTCAE: Common Terminology Criteria for Adverse Events

Table 2: Recommended dose adjustments for Vargatef (nintedanib) in case of AST and/or ALTand bilirubin elevations

AST/ALT and bilirubin elevations Dose adjustment

Elevation of AST and/or ALT values After treatment interruption and recovery ofto > 2.5 × ULN in conjunction with total bilirubin transaminase-values to ≤ 2.5 × ULN inelevation to ≥ 1.5 × ULN conjunction with bilirubin to normal, dose

OR reduction from 200 mg twice daily to 150 mg

Elevation of AST and/or ALT values twice daily and - if a 2nd dose reduction isto > 5 × ULN considered necessary - from 150 mg twice dailyto 100 mg twice daily.

Elevation of AST and/or ALT values Unless there is an alternative cause established,to > 3 × ULN in conjunction with an increase of Vargatef should be permanently discontinuedtotal bilirubin to ≥ 2 × ULN and

ALKP < 2 × ULN

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase

ALKP: Alkaline phosphatase; ULN: Upper limit normal

The safety and efficacy of Vargatef in children aged 0-18 years have not been established.

Elderly patients (≥ 65 years)

No overall differences in safety and efficacy were observed for elderly patients.

In the pivotal trial 1199.13, 85 patients (12.9% of the patients with adenocarcinoma histology)were ≥ 70 years of age (median age: 72 years, range: 70-80 years) (see section 5.1).

No adjustment of the initial dosing is required in elderly patients (see section 5.2).

Race and body weight

Based on population pharmacokinetic (PK) analyses, no a priori dose adjustments of Vargatef arenecessary (see section 5.2). Safety data for Black and African American patients are limited.

Less than 1% of a single dose of nintedanib is excreted via the kidney (see section 5.2). Adjustment ofthe 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 renalimpairment (< 30 mL/min creatinine clearance).

Nintedanib is predominantly eliminated via biliary/faecal excretion (> 90%). Exposure increased inpatients with hepatic impairment (Child Pugh A, Child Pugh B; see section 5.2). No adjustment of thestarting dose is needed for patients with mild hepatic impairment (Child Pugh A) based on clinicaldata. Limited safety data available from 9 patients with moderate hepatic impairment (Child Pugh B)are insufficient to characterize this population. The safety, efficacy and pharmacokinetics ofnintedanib have not been investigated in patients with severe hepatic impairment (Child Pugh C).

Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairmentwith Vargatef is not recommended (see sections 4.4 and 5.2).

Vargatef capsules must be taken orally, preferably with food, swallowed whole with water, and mustnot be chewed. The capsule should not be opened or crushed (see section 6.6).

Hypersensitivity to nintedanib, to peanut or soya, or to any of the excipients listed in section 6.1.

Diarrhoea was the most frequently reported gastro-intestinal adverse reaction and appeared in closetemporal relationship with the administration of docetaxel (see section 4.8). In the clinical trial

LUME-Lung 1 (see section 5.1), the majority of patients had mild to moderate diarrhoea.

Serious cases of diarrhoea leading to dehydration and electrolyte disturbances have been reported withnintedanib in the post-marketing period. Diarrhoea should be treated at first signs with adequatehydration and anti-diarrhoeal medicinal products, for example loperamide, and may requireinterruption, dose reduction or discontinuation of therapy with Vargatef (see section 4.2).

Nausea and vomiting, mostly of mild to moderate severity, were frequently reported gastrointestinaladverse reactions (see section 4.8). Interruption, dose reduction or discontinuation of therapy with

Vargatef (see section 4.2) may be required despite appropriate supportive care. Supportive care fornausea and vomiting may include medicinal products with anti-emetic properties, e.g. glucocorticoids,anti-histamines or 5-HT3 receptor antagonists and adequate hydration.

In the event of dehydration, administration of electrolytes and fluids is required. Plasma levels ofelectrolytes should be monitored, if relevant gastrointestinal adverse events occur. Interruption, dosereduction or discontinuation of therapy with Vargatef may be required (see section 4.2).

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 (including fatalcases).

Blood counts should be monitored during therapy, in particular during the combination treatment withdocetaxel. Frequent monitoring of complete blood counts should be performed at the beginning ofeach treatment cycle and around the nadir for patients receiving treatment with nintedanib incombination with docetaxel, and as clinically indicated after the administration of the last combinationcycle.

Hepatic function

Based on increased exposure, the risk for adverse events may be increased in patients with mildhepatic impairment (Child Pugh A; see sections 4.2 and 5.2). Limited safety data are available in9 patients with hepatocellular carcinoma and moderate hepatic impairment classified as Child Pugh B.

Although no unexpected safety findings were reported in these patients, the data are insufficient tosupport a recommendation for treatment of patients with moderate hepatic impairment. The efficacy ofnintedanib has not been investigated in patients with moderate hepatic impairment (Child Pugh B).

The safety, efficacy and pharmacokinetics of nintedanib have not been studied in patients with severehepatic impairment (Child Pugh C). Treatment with Vargatef is not recommended in patients withmoderate or severe hepatic impairment (see section 4.2).

Cases of drug-induced liver injury have been observed with nintedanib treatment, including severeliver injury with fatal outcome. Elevation of liver enzymes (ALT, AST, ALKP,gamma-glutamyltransferase (GGT)) and bilirubin were reversible upon dose reduction or interruptionin the majority of cases.

Transaminase, ALKP and bilirubin levels should be investigated before initiation of the combinationtreatment with Vargatef plus docetaxel. The values should be monitored as clinically indicated orperiodically during treatment, i.e. in the combination phase with docetaxel at the beginning of eachtreatment cycle and monthly in case Vargatef is continued as monotherapy after discontinuation ofdocetaxel.

If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of thetherapy with Vargatef may be required (see section 4.2). Alternative causes of the liver enzymeelevations should be investigated and respective action should be taken as necessary. In case ofspecific changes in liver values (AST/ALT > 3 × ULN; total bilirubin ≥ 2 × ULN and

ALKP < 2 × ULN) treatment with Vargatef should be interrupted. Unless there is an alternative causeestablished, Vargatef should be permanently discontinued (see section 4.2).

Patients with low body weight (< 65 kg), Asian and female patients have a higher risk of elevations inliver enzymes. Nintedanib exposure increased linearly with patient age, which may also result in ahigher risk of developing liver enzyme elevations (see section 5.2). Close monitoring is recommendedin patients with these risk factors.

Cases of renal impairment/failure, in some cases with fatal outcome, have been reported withnintedanib use (see section 4.8).

Patients should be monitored during nintedanib therapy, with particular attention to those patientsexhibiting risk factors for renal impairment/failure. In case of renal impairment/failure, therapyadjustment should be considered (see section 4.2 Dose adjustments).

VEGFR inhibition might be associated with an increased risk of bleeding. In the clinical trial(LUME-Lung 1; see section 5.1) with Vargatef, the frequency of bleeding in both treatment arms wascomparable (see section 4.8). Mild to moderate epistaxis represented the most frequent bleeding event.

The majority of fatal bleeding events were tumour-associated. There were no imbalances ofrespiratory or fatal bleedings and no intracerebral bleeding was reported.

Patients with recent pulmonary bleeding (> 2.5 mL of red blood) as well as patients with centrallylocated tumours with radiographic evidence of local invasion of major blood vessels or radiographicevidence of cavitary or necrotic tumours have been excluded from clinical trials. Therefore, it is notrecommended to treat these patients with Vargatef.

Non-serious and serious bleeding events, some of which were fatal, have been reported in thepost-marketing period, including patients with or without anticoagulant therapy or other medicinalproducts that could cause bleeding (for clinical trials’ data, see also ‘Therapeutic anticoagulation’below). In case of bleeding, dose adjustment, interruption or discontinuation should be consideredbased on clinical judgement (see section 4.2). Post-marketing bleeding events include but are notlimited to gastrointestinal, respiratory and central nervous system organs, with the most frequent beingrespiratory.

Therapeutic anticoagulation

There are no data available from clinical trials for patients with inherited predisposition to bleeding orfor patients receiving a full dose of anticoagulative treatment prior to start of treatment with Vargatef(for post-marketing experience, see ‘Haemorrhage’ above). In patients on chronic low dose therapywith low molecular weight heparins or acetylsalicylic acid, no increased frequency of bleeding wasobserved. Patients who developed thromboembolic events during treatment and who requiredanticoagulant treatment were allowed to continue Vargatef and did not show an increased frequency ofbleeding events. Patients taking concomitant anticoagulation, such as warfarin or phenprocoumonshould be monitored regularly for changes in prothrombin time, international normalised ratio (INR),and clinical bleeding episodes.

Brain metastasis

Stable brain metastasis

No increased frequency of cerebral bleeding in patients with adequately pre-treated brain metastaseswhich were stable for ≥ 4 weeks before start of treatment with Vargatef was observed. However, suchpatients 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 fortreatment with Vargatef.

Patients treated with Vargatef have an increased risk of venous thromboembolism includingpulmonary embolism and deep vein thrombosis. Patients should be closely monitored forthromboembolic events. Caution should be used especially in patients with additional risk factors forthromboembolic events. Vargatef should be discontinued in patients with life-threatening venousthromboembolic reactions.

The frequency of arterial thromboembolic events was comparable between the two treatment arms inthe phase 3 trial 1199.13 (LUME-Lung 1). Patients with a recent history of myocardial infarction orstroke were excluded from this trial. However, an increased frequency of arterial thromboembolicevents was observed in patients with idiopathic pulmonary fibrosis (IPF) when treated with nintedanibmonotherapy. Use caution when treating patients with a higher cardiovascular risk including knowncoronary artery disease. Treatment interruption should be considered in patients who develop signs orsymptoms of acute myocardial ischaemia.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote theformation of aneurysms and/or artery dissections. Before initiating Vargatef, this risk should becarefully considered in patients with risk factors such as hypertension or history of aneurysm.

Gastrointestinal perforations and ischaemic colitis

The frequency of gastrointestinal perforation was comparable between the treatment arms in theclinical trial. However, based on the mechanism of action patients treated with Vargatef may have anincreased risk of gastrointestinal perforations. Cases of gastrointestinal perforations and ischaemiccolitis, some of which were fatal, have been reported in the post-marketing period under nintedanib.

Particular caution should be exercised when treating patients with previous abdominal surgery or arecent history of a hollow organ perforation. Vargatef should therefore only be initiated atleast 4 weeks after major surgery. Therapy with Vargatef should be permanently discontinued inpatients who develop gastrointestinal perforation. In patients who develop ischaemic colitis Vargatefshould be discontinued, and exceptionally, Vargatef can be reintroduced after complete resolution ofischaemic colitis and careful assessment of patient’s condition and other risk factors.

Nephrotic range proteinuria

Very few cases of nephrotic range proteinuria have been reported post-marketing. Histologicalfindings in individual cases were consistent with glomerular microangiopathy with or without renalthrombi. Reversal of symptoms has been observed after Vargatef was discontinued. Treatmentinterruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.

Posterior reversible encephalopathy syndrome (PRES)

Some cases of posterior reversible encephalopathy syndrome (PRES) have been reported post-marketing.

PRES is a neurological disorder (confirmed with magnetic resonance imaging) which can present withheadache, hypertension, visual disturbances, seizure, lethargy, confusion and other visual andneurologic disturbances, and can be fatal. PRES has been reported with other VEGF inhibitors.

If PRES is suspected, nintedanib treatment must be discontinued. Reinitiating nintedanib therapy inpatients previously experiencing PRES is not known and should be left to the physician’srecommendation.

Wound healing complication

Based on the mechanism of action nintedanib may impair wound healing. No increased frequency ofimpaired wound healing was observed in the LUME-Lung 1 trial. No dedicated trials investigating theeffect of nintedanib on wound healing were performed. Treatment with Vargatef should therefore onlybe initiated or - in case of perioperative interruption - resumed based on clinical judgement ofadequate wound healing.

No QT prolongation was observed for nintedanib in the clinical trial program (see section 5.1).

As several other tyrosine kinase inhibitors are known to exert an effect on QT, caution should beexercised when administering nintedanib in patients who may develop QTc prolongation.

Allergic reaction

Dietary soya-products are known to cause allergic reactions including severe anaphylaxis in personswith soya allergy. Patients with known allergy to peanut protein carry an enhanced risk for severereactions to soya preparations.

In trial 1199.13 (LUME-Lung 1), there was a higher frequency of SAEs in patients treated withnintedanib plus docetaxel with a body weight of less than 50 kg compared to patients with aweight ≥ 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.

Interaction studies have only been performed in adults.

P-glycoprotein (P-gp)

Nintedanib is a substrate of P-gp (see section 5.2). Co-administration with the potent P-gp inhibitorketoconazole increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on Cmax ina dedicated drug-drug interaction study. In a drug-drug interaction study with the potent P-gp inducerrifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on Cmaxupon co-administration with rifampicin compared to administration of nintedanib alone. Ifco-administered with nintedanib, potent P-gp inhibitors (e.g. ketoconazole or erythromycin) mayincrease exposure to nintedanib. In such cases, patients should be monitored closely for tolerability ofnintedanib. Management of adverse reactions may require interruption, dose reduction, ordiscontinuation of therapy with Vargatef (see section 4.2).

Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decreaseexposure to nintedanib. Co-administration with nintedanib should be carefully considered.

Cytochrome (CYP)-enzymes

Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways. Nintedaniband its metabolites, the free acid moiety BIBF 1202 and its glucuronide BIBF 1202 glucuronide, didnot inhibit or induce CYP enzymes in preclinical studies (see section 5.2). The likelihood of drug-druginteractions with nintedanib based on CYP metabolism is therefore considered to be low.

Co-administration with other medicinal products

Co-administration of nintedanib with docetaxel (75 mg/m²) did not alter the pharmacokinetics of eithermedicinal product to a relevant extent.

Co-administration of nintedanib with oral hormonal contraceptives did not alter the pharmacokineticsof oral hormonal contraceptives to a relevant extent (see section 5.2).

Nintedanib may cause foetal harm in humans (see section 5.3). Women of childbearing potentialshould be advised to avoid becoming pregnant while receiving treatment with Vargatef and to usehighly effective contraceptive methods at initiation of, during and at least 3 months after the last doseof Vargatef. Nintedanib does not relevantly affect the plasma exposure of ethinylestradiol andlevonorgestrel (see section 5.2). The efficacy of oral hormonal contraceptives may be compromised byvomiting and/or diarrhoea or other conditions where the absorption may be affected. Women takingoral hormonal contraceptives experiencing these conditions should be advised to use an alternativehighly effective contraceptive measure.

There is no information on the use of Vargatef in pregnant women, but preclinical studies in animalshave shown reproductive toxicity of this active substance (see section 5.3). As nintedanib may causefoetal harm also in humans, it should not be used during pregnancy unless the clinical conditionrequires treatment. Pregnancy testing should be conducted at least prior to treatment with Vargatef.

Female patients should be advised to notify their doctor or pharmacist if they become pregnant duringtherapy with Vargatef.

If the patient becomes pregnant while receiving Vargatef, she should be apprised of the potentialhazard to the foetus. Termination of the treatment with Vargatef should be considered.

There is no information on the excretion of nintedanib and its metabolites in human milk.

Preclinical studies showed that small amounts of nintedanib and its metabolites (≤ 0.5% of theadministered dose) were secreted into milk of lactating rats. A risk to the breast-fed child cannot beexcluded. Breast-feeding should be discontinued during treatment with Vargatef.

Based on preclinical investigations there is no evidence for impairment of male fertility(see section 5.3). There are no human or animal data on potential effects of nintedanib on femalefertility available.

Vargatef has minor influence on the ability to drive and use machines. Patients should be advised to becautious when driving or using machines during treatment with Vargatef.

The safety data provided in the sections below are based on the global, double-blind randomisedpivotal phase 3 trial 1199.13 (LUME-Lung 1) comparing treatment with nintedanib plus docetaxelagainst placebo plus docetaxel in patients with locally advanced, or metastatic, or recurrent NSCLCafter first-line chemotherapy and based on data observed during the post-marketing period. The mostfrequently reported adverse drug reactions (ADRs) specific for nintedanib were diarrhoea, increasedliver enzyme values (ALT and AST) and vomiting. Table 3 provides a summary of the adversereactions by System Organ Class (SOC). For the management of selected adverse reactions, seesection 4.4. Information about selected adverse reactions observed from the LUME-Lung 1 trial aredescribed below.

Table 3 summarizes the frequencies of adverse drug reactions that were reported in the pivotal trial

LUME-Lung 1 for patients with NSCLC of adenocarcinoma tumour histology (n = 320) or from thepost-marketing period. 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.

Table 3: Summary of ADRs per frequency category

System Organ Very common Common Uncommon Not known

Class (≥ 1/10) (≥ 1/100 < 1/10) (≥ 1/1 000< 1/100)

Infections and Febrile neutropenia,infestations Abscesses,

Blood and Neutropenia Thrombocytopenialymphatic system (includes febriledisorders neutropenia)

Metabolism and Decreased Dehydration,nutrition appetite, Weight decreaseddisorders Electrolyteimbalance

Nervous system Peripheral Headache1) Posteriordisorders neuropathy reversibleencephalopathysyndrome

Cardiac disorders Myocardialinfarction (seesection 4.4)

Vascular Bleeding1) Venous Aneurysms anddisorders (see section 4.4) thromboembolism3), artery

Hypertension dissections

Gastrointestinal Diarrhoea, Perforation1) Colitisdisorders Vomiting, Pancreatitis2)

Nausea,

Abdominal pain

Hepatobiliary Alanine Hyperbilirubinaemia, Drug-induceddisorders aminotransferase Gamma-glutamyltran liver injury(ALT) sferase (GGT)increased, increased

Aspartateaminotransferase(AST) increased,

Blood alkalinephosphatase(ALKP)increased

Skin and Mucositis Pruritussubcutaneous (includingtissue disorders stomatitis),

Rash,

Alopecia1)

Renal and urinary Proteinuria1) Renal failuredisorders (see section 4.4)1) In clinical trials the frequency was not increased in patients treated with nintedanib plus docetaxel ascompared to placebo plus docetaxel.

2) Events of pancreatitis have been reported in patients taking nintedanib for the treatment of IPF and NSCLC.

The majority of these events were reported for patients in the IPF indication.

3) Cases of pulmonary embolism have been reported.

Diarrhoea occurred in 43.4% (≥ grade 3: 6.3%) of adenocarcinoma patients in the nintedanib arm. Themajority of adverse reactions appeared in close temporal relationship with the administration ofdocetaxel. Most patients recovered from diarrhoea following treatment interruption, anti-diarrhoealtherapy and nintedanib dose reduction.

For recommended measures and dosing adjustments in case of diarrhoea, see sections 4.4 and 4.2,respectively.

Liver enzyme elevations and hyperbilirubinaemia

Liver-related adverse reactions occurred in 42.8% of nintedanib-treated patients. Approximately onethird of these patients had liver-related adverse reactions of ≥ grade 3 severity. In patients withincreased liver parameters, the use of the established stepwise dose reduction scheme was theappropriate measure and discontinuation of treatment was only necessary in 2.2% of patients. In themajority of patients, elevations of liver parameters were reversible.

For information about special populations, recommended measures and dosing adjustments in case ofliver enzyme and bilirubin elevations, see sections 4.4 and 4.2, respectively.

Neutropenia, febrile neutropenia and sepsis

Sepsis and febrile neutropenia have been reported as subsequent complications of neutropenia. Therates of sepsis (1.3%) and febrile neutropenia (7.5%) were increased under treatment with nintedanibas compared to the placebo arm. It is important that the patient’s blood counts are monitored duringtherapy, in particular during the combination treatment with docetaxel (see section 4.4).

In the post-marketing period non-serious and serious bleeding events, some of which fatal, have beenreported, including patients with or without anticoagulant therapy or other medicinal products thatcould 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 alsosection 4.4).

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 is also known to occur with docetaxel treatment. Peripheral neuropathy wasreported in 16.5% of patients in the placebo arm and in 19.1% of patients in the nintedanib arm.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote or treatment for nintedanib overdose. The highest single dose ofnintedanib administered in phase I studies was 450 mg once daily. In addition, 2 patients had anoverdose of maximum 600 mg twice daily (b.i.d.) up to eight days. Observed adverse events wereconsistent with the known safety profile of nintedanib, i.e. increased liver enzymes and gastrointestinalsymptoms. Both patients recovered from these adverse reactions. In case of overdose, treatment shouldbe interrupted and general supportive measures initiated as appropriate.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EX09

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 factorreceptors (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 theproliferation and survival of endothelial as well as perivascular cells (pericytes and vascular smoothmuscle cells). In addition Fms-like tyrosine-protein kinase (Flt)-3, lymphocyte-specifictyrosine-protein kinase (Lck) and proto-oncogene tyrosine-protein kinase Src (Src) are inhibited.

Tumour angiogenesis is an essential feature contributing to tumour growth, progression and metastasisformation and is predominantly triggered by the release of pro-angiogenic factors secreted by thetumour cell (i.e. VEGF and bFGF) to attract host endothelial as well as perivascular cells to facilitateoxygen 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 vascularsystem resulting in tumour growth inhibition and tumour stasis. In particular, treatment of tumourxenografts with nintedanib led to a rapid reduction in tumour micro vessel density, pericytes vesselcoverage and tumour perfusion.

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) measurements showed ananti-angiogenic effect of nintedanib in humans. It was not clearly dose dependent, but most responseswere seen at doses of ≥ 200 mg. Logistic regression revealed a statistically significant association ofthe anti-angiogenic effect to nintedanib exposure. DCE-MRI effects were seen 24-48 h after the firstintake of the medicinal product and were preserved or even increased after continuous treatment overseveral weeks. No correlation of the DCE-MRI response and subsequent clinically significantreduction in target lesion size was found, but DCE-MRI response was associated with diseasestabilization.

Efficacy in the pivotal phase 3 trial LUME-Lung 1

The efficacy and safety of Vargatef was investigated in 1 314 adult patients with locally advanced,metastatic or recurrent NSCLC after one prior line of chemotherapy. ‘Locally recurrent’ was definedas local re-occurrence of the tumour without metastases at trial entry. The trial included 658 patients(50.1%) with adenocarcinoma, 555 patients (42.2%) with squamous cell carcinoma, and101 patients (7.7%) with other tumour histologies.

Patients were randomised (1:1) to receive nintedanib 200 mg orally twice daily in combination with75 mg/m2 of intravenous docetaxel every 21 days (n = 655) or placebo orally twice daily incombination with 75 mg/m2 of docetaxel every 21 days (n = 659). Randomization was stratifiedaccording to Eastern Cooperative Oncology Group (ECOG) status (0 versus 1), bevacizumabpretreatment (yes versus no), brain metastasis (yes versus no) and tumour histology (squamous versusnon-squamous tumour histology).

Patient characteristics were balanced between treatment arms within the overall population and withinsubgroups according to histology. In the overall population, 72.7% of the patients were male. Themajority of patients were non-Asian (81.6%), the median age was 60.0 years, the baseline ECOGperformance status was 0 (28.6%) or 1 (71.3%); one patient had a baseline ECOG performance statusof 2. Five point eight percent (5.8%) of the patients had stable brain metastasis at trial 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 overallpopulation, 16.0% of the patients had disease stage < IIIB/IV, 22.4%, had disease stage IIIB and61.6% had disease stage IV. 9.2% of the patients entered the trial with locally recurrent disease stageas had been evaluated at baseline. For patients with tumour of adenocarcinoma histology, 15.8% haddisease stage < IIIB/IV, 15.2%, had disease stage IIIB and 69.0% had disease stage IV.5.8% of the adenocarcinoma patients entered the trial with locally recurrent disease stage as had beenevaluated at baseline.

The primary endpoint was progression-free survival (PFS) as assessed by an independent reviewcommittee (IRC) based on the intent-to-treat (ITT) population and tested by histology. Overallsurvival (OS) was the key secondary endpoint. Other efficacy outcomes included objective response,disease control, change in tumour size and health-related quality of life.

The addition of nintedanib to docetaxel led to a statistically significant reduction in the risk ofprogression or death by 21% for the overall population (hazard ratio (HR) 0.79; 95% confidenceinterval (CI): 0.68-0.92; p = 0.0019) as determined by the Independent Review Committee. This resultwas confirmed in the follow-up PFS analysis (HR 0.85, 95% CI: 0.75-0.96; p = 0.0070) whichincluded all events collected at the time of the final OS analysis. Overall survival analysis in theoverall 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 OSbetween treatment arms in the adenocarcinoma population only (Table 4).

As shown in Table 4, the addition of nintedanib to docetaxel led to a statistically significant reductionin 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 trial endpoints such as disease control andchange in tumour size showed significant improvements.

Table 4: Efficacy results for trial LUME-Lung 1 for patients with adenocarcinoma tumourhistology

Vargatef + Docetaxel Placebo + Docetaxel

Progression free survival (PFS)* - primary analysis

Patients, n 277 285

Number of Deaths or Progressions, n (%) 152 (54.9) 180 (63.2)

Median PFS [months] 4.0 2.8

HR (95% CI) 0.77 (0.62; 0.96)

Stratified Log-Rank Test p-value** 0.0193

Progression free survival (PFS)*** - follow-up analysis

Patients, n 322 336

Number of Deaths or Progressions, n (%) 255 (79.2) 267 (79.5)

Median PFS [months] 4.2 2.8

HR (95% CI) 0.84 (0.71; 1.00)

Stratified Log-Rank Test p-value** 0.0485

Disease control [%] 60.2 44.0

Odds ratio (95% CI)+ 1.93 (1.42; 2.64)p-value+ < 0.0001

Objective response [%] 4.7 3.6

Odds ratio (95% CI)+ 1.32 (0.61; 2.93)p-value+ 0.4770

Tumour shrinkage [%]° -7.76 -0.97p-value° 0.0002

Overall Survival (OS)***

Patients, n 322 336

Number of Deaths, n (%) 259 (80.4) 276 (82.1)

Median OS [months] 12.6 10.3

HR (95% CI) 0.83 (0.70; 0.99)

Stratified Log-Rank Test p-value* 0.0359

HR: hazard ratio; CI: confidence interval

* Primary PFS analysis performed when 713th PFS events had been observed based on IRC-assessment in theoverall ITT population (332 events in adenocarcinoma patients).

** Stratified by baseline ECOG PS (0 versus 1), brain metastases at baseline (yes versus no) and prior treatmentwith bevacizumab (yes versus no).

*** OS analysis and follow-up PFS-analysis performed when 1 121 death cases had been observed in the overall

ITT population (535 events in adenocarcinoma patients).+ Odds ratio and p-value were obtained from a logistic regression model adjusted for baseline ECOG

Performance Score (0 versus 1).° Adjusted mean of best-% change from baseline and p-value generated from an ANOVA model adjusting forbaseline ECOG PS (0 versus 1), brain metastases at baseline (yes versus no) and prior treatment withbevacizumab (yes versus no).

A statistically significant improvement in OS favouring treatment with nintedanib plus docetaxel wasdemonstrated 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 versus 12.6 months, Figure 1).

Figure 1: Kaplan-Meier curve for overall survival for patients with adenocarcinoma tumourhistology by treatment group in trial LUME-Lung 1

Median (months)52.7%44.7%25.7%19.1%

Time (months)

No. of patients at risk

Placebo

Nintedanib

A pre-specified evaluation was performed in the population of adenocarcinoma patients considered tohave entered the trial with a particularly poor treatment prognosis, namely, patients who progressedduring or shortly after first-line therapy prior to trial entry. This population included thoseadenocarcinoma patients identified at baseline as having progressed and entered the trial less than9 months since start of their first-line therapy. Treatment of these patients with nintedanib incombination 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 havingprogressed and entered the trial ≥ 9 months since start of their first-line therapy the difference did notreach 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 balancedacross treatment arms (placebo: 54 patients (16.1%); nintedanib: 50 patients, (15.5%)). The HR forthese 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 waswide and included the HR for OS of the overall adenocarcinoma population.

Treatment with nintedanib did not significantly change the time to deterioration of the pre-specifiedsymptoms cough, dyspnoea and pain, but resulted in a significant deterioration in the diarrhoeasymptom scale. Nevertheless, the overall treatment benefit of nintedanib was observed withoutadversely affecting self-reported quality of life.

QT/QTc measurements were recorded and analysed from a dedicated trial comparing nintedanibmonotherapy against sunitinib monotherapy in patients with renal cell carcinoma. In this trial singleoral doses of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administeredtwice daily for 15 days did not prolong the QTcF interval. However, no thorough QT-trial ofnintedanib administered in combination with docetaxel was conducted.

Probability of survival (%)

The European Medicines Agency has waived the obligation to submit the results of studies with

Vargatef in all subsets of the paediatric population in non-small cell lung cancer (see section 4.2 forinformation on paediatric use).

Nintedanib reached maximum plasma concentrations approximately 2-4 hours after oraladministration as soft gelatin capsule under fed conditions (range 0.5-8 hours). The absolutebioavailability of a 100 mg dose was 4.69% (90% CI: 3.615-6.078) in healthy volunteers. Absorptionand bioavailability are decreased by transporter effects and substantial first-pass metabolism.

Nintedanib exposure increased dose-proportionally in the dose range of 50-450 mg once daily and150-300 mg twice daily. Steady state plasma concentrations were achieved within one week of dosingat the latest.

After food intake, nintedanib exposure increased by approximately 20% compared to administrationunder fasted conditions (CI: 95.3-152.5%) and absorption was delayed (median tmax fasted: 2.00 hours;fed: 3.98 h).

In an in vitro study, mixing nintedanib capsules with a small amount of apple sauce or chocolatepudding for up to 15 minutes did not have any impact on the pharmaceutical quality. Swelling anddeformation of the capsules due to the water uptake of the gelatin capsule shell was observed withlonger exposure time to the soft food. Therefore, taking the capsules with soft food would not beexpected to alter the clinical effect when taken immediately.

Nintedanib follows at least bi-phasic disposition kinetics. After intravenous infusion, a high volume ofdistribution (Vss: 1 050 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 distributedin plasma with a blood to plasma ratio of 0.869.

The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the freeacid 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 3A4being the predominant enzyme involved. The major CYP-dependent metabolite could not be detectedin 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 targetreceptors of the substance.

Total plasma clearance after intravenous infusion was high (CL: 1 390 mL/min, 28.8% gCV). Urinaryexcretion of the unchanged active substance within 48 h was about 0.05% of the dose (31.5% gCV)after oral and about 1.4% of dose (24.2% gCV) after intravenous administration; the renal clearancewas 20 mL/min (32.6% gCV). The major route of elimination of drug related radioactivity after oraladministration 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 terminalhalf-life of nintedanib was between 10 and 15 h (gCV% approximately 50%).

The pharmacokinetics of nintedanib can be considered linear with respect to time (i.e. single-dose datacan be extrapolated to multiple-dose data). Accumulation upon multiple administrations was 1.04-foldfor Cmax and 1.38-fold for AUCτ. Nintedanib trough concentrations remained stable for more than oneyear.

Other information on drug-drug interactions

Drug-drug interactions between nintedanib and CYP substrates, CYP inhibitors, or CYP inducers arenot expected, since nintedanib, BIBF 1202, and BIBF 1202 glucuronide did not inhibit or induce

CYP enzymes in preclinical studies nor was nintedanib metabolized by CYP enzymes to a relevantextent.

Transport

Nintedanib is a substrate of P-gp. For the interaction potential of nintedanib with this transporter, seesection 4.5. 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 weakinhibitory potential on OCT-1, BCRP, and P-gp was observed in vitro which is considered to be oflow clinical relevance. The same applies for nintedanib being a substrate of OCT-1.

In exploratory pharmacokinetic adverse event analyses, higher exposure to nintedanib tended to beassociated with liver enzyme elevations, but not with gastrointestinal adverse events.

PK-efficacy analyses were not performed for clinical endpoints. Logistic regression revealed astatistically significant association between nintedanib exposure and DCE-MRI response.

Population pharmocokinetic analysis in special populations

The pharmacokinetic properties of nintedanib were similar in healthy volunteers, cancer patients, andpatients of the target population. Exposure to nintedanib was not influenced by gender (body weightcorrected), mild and moderate renal impairment (estimated by creatinine clearance), liver metastases,

ECOG performance score, alcohol consumption, and P-gp genotype.

Population PK analyses indicated moderate effects on exposure to nintedanib depending on age, bodyweight, and race (see below). Based on the high inter-individual variability of exposure observed inthe clinical LUME-Lung-1 trial these effects are not considered clinically relevant. However, closemonitoring is recommended in patients with several of these risk factors (see section 4.4).

Exposure to nintedanib increased linearly with age. AUCτ,ss decreased by 16% for a 45-year oldpatient (5th percentile) and increased by 13% for a 76-year old patient (95th percentile) relative to apatient with the median age of 62 years. The age range covered by the analysis was 29 to 85 years;approximately 5% of the population were older than 75 years.

An inverse correlation between body weight and exposure to nintedanib was observed. AUCτ,ssincreased 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.

The population mean exposure to nintedanib was 33-50% higher in Chinese, Taiwanese, and Indianpatients and 16% higher in Japanese patients while it was 16-22% lower in Koreans compared to

Caucasians (body weight corrected). Based on the high inter-individual variability of exposure theseeffects are not considered clinically relevant. Data from black individuals was very limited but in thesame range as for Caucasians.

In a dedicated single dose phase I trial and compared to healthy subjects, exposure to nintedanib basedon 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 hepaticimpairment (Child Pugh B), exposure was 7.6-fold higher based on Cmax (90% CI 4.4-13.2) and8.7-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 oral hormonal contraceptives

In a dedicated pharmacokinetic study, female patients with SSc-ILD received a single dose of acombination of 30 µg ethinylestradiol and 150 µg levonorgestrel before and after twice daily dosing of150 mg nintedanib for at least 10 days. The adjusted geometric mean ratios (90% confidence interval(CI)) were 117% (108% - 127%; Cmax) and 101% (93% - 111%; AUC0-tz) for ethinylestradiol and101% (90% - 113%; Cmax) and 96% (91% - 102%; AUC0-tz) for levonorgestrel, respectively (n = 15),indicating that co-administration of nintedanib has no relevant effect on the plasma exposure ofethinylestradiol and levonorgestrel.

General toxicology

Single dose toxicity studies in rats and mice indicated a low acute toxic potential of nintedanib. Inrepeat dose toxicology studies in rats, adverse effects (e.g. thickening of epiphyseal plates, lesions ofthe 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 wereobserved in toxicity studies in non-rodents.

There was no evidence of liver enzyme increases in rats, dogs, and Cynomolgus monkeys. Mild liverenzyme increases, which were not due to serious adverse effects such as diarrhoea, were onlyobserved in Rhesus monkeys.

Reproduction toxicity

A study of male fertility and early embryonic development to implantation in rats did not revealeffects on the male reproductive tract and male fertility.

In rats, embryofoetal lethality and teratogenic effects were observed at exposure levels below humanexposure, at the maximum recommended human dose (MRHD) of 200 mg b.i.d. Effects on thedevelopment of the axial skeleton and on the development of the great arteries were also noted atsubtherapeutic exposure levels.

In rabbits, embryofoetal lethality was observed at an exposure approximately 8 times higher than atthe MRHD. Teratogenic effects on the aortic arches in combination with the heart and the urogenitalsystem were noted at an exposure 4 times higher than at the MRHD and on the embryofoetaldevelopment of the axial skeleton at an exposure 3 times higher than at the MRHD.

In rats, small amounts of radiolabelled nintedanib and/or its metabolites were excreted into the milk(≤ 0.5% of the administered dose).

Genotoxicity studies indicated no mutagenic potential for nintedanib.

Triglycerides, medium-chain

Hard fat

Soya lecithin (E322)

Gelatin

Glycerol (85%)

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Not applicable.

3 years.

Do not store above 25 °C.

Store in the original package in order to protect from moisture.

Aluminium/aluminium blisters containing 10 capsules each.

Vargatef 100 mg soft capsules

Pack-sizes: 60 or 120 capsules, or multipack of 120 (2 × 60) capsules (2 cartons of 60 capsules each,wrapped in plastic foil).

Vargatef 150 mg soft capsules

Pack-size: 60 capsules.

Not all pack-sizes may be marketed.

In the event of coming in contact with the content of the capsule, hands should be washed offimmediately with plenty of water (see section 4.2).

Any unused product or waste material should be disposed of in accordance with local requirements.

Boehringer Ingelheim International GmbH

Binger Strasse 17355216 Ingelheim am Rhein

Germany

Vargatef 100 mg soft capsules

EU/1/14/954/001

EU/1/14/954/002

EU/1/14/954/003

Vargatef 150 mg soft capsules

EU/1/14/954/004

Date of first authorisation: 21 November 2014

Date of latest renewal: 26 August 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.