Vargatef

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Vargatef 100 mg soft capsules
Vargatef 150 mg soft capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Vargatef 100 mg soft capsules
Each soft capsule contains 100 mg nintedanib (as esilate).
Excipients with known effect
Each capsule contains 1.2 mg of soya lecithin.

Vargatef 150 mg soft capsules
Each soft capsule contains 150 mg nintedanib (as esilate).
Excipients with known effect
Each capsule contains 1.8 mg of soya lecithin.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Soft capsule (capsule).

Vargatef 100 mg soft capsules
Peach-coloured, opaque, oblong soft-gelatin capsules imprinted on one side in black with the 
Boehringer Ingelheim company symbol and “100”.

Vargatef 150 mg soft capsules
Brown-coloured, opaque, oblong soft-gelatin capsule imprinted on one side in black with the 
Boehringer Ingelheim company symbol and “150”.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

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



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

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

Dose adjustments
As initial measure for the management of adverse reactions (see Tables 1 and 2) treatment with 
nintedanib should be temporarily interrupted until the specific adverse reaction has resolved to levels 
that 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 as 
described 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 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 2) treatment with Vargatef should be interrupted. Unless there is an 
alternative cause established, Vargatef should be permanently discontinued (see also section 4.4).

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

CTCAE* Adverse reaction Dose adjustment

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

OR

Diarrhoea ≥ grade 3 despite anti-diarrhoeal 
treatment After treatment interruption and recovery to 

grade 1 or baseline, dose reduction from 200 mg
twice daily to 150 mg twice daily and 
- if a 2nd dose reduction is considered 
necessary - from 150 mg twice daily to 100 mg
twice daily.

Vomiting ≥ grade 2 

AND/OR

Nausea ≥ grade 3 

despite anti-emetic treatment

Other non-haematological or haematological 
adverse reaction of ≥ grade 3

* CTCAE: Common Terminology Criteria for Adverse Events



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

AST / ALT and bilirubin elevations Dose adjustment

Elevation of AST and/or ALT values 
to > 2.5 x ULN in conjunction with total bilirubin 
elevation to ≥ 1.5 x ULN

  OR

Elevation of AST and/or ALT values 
to > 5 x ULN

After treatment interruption and recovery of 
transaminase-values to ≤ 2.5 x ULN in 
conjunction with bilirubin to normal, dose 
reduction from 200 mg twice daily to 150 mg
twice daily and - if a 2nd dose reduction is 
considered necessary - from 150 mg twice daily 
to 100 mg twice daily.

Elevation of AST and/or ALT values 
to > 3 x ULN in conjunction with an increase of 
total bilirubin to ≥ 2 x ULN and 
ALKP < 2 x ULN

Unless there is an alternative cause established, 
Vargatef should be permanently discontinued 

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase
ALKP: Alkaline phosphatase; ULN: Upper limit normal

Special populations

Paediatric population
The safety and efficacy of Vargatef in children aged 0-18 years have not been established. No data are 
available.

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 on the basis of a patient’s age (see section 5.2).

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

Renal impairment
Less than 1 % of a single dose of nintedanib is excreted via the kidney (see section 5.2). 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 creatinine clearance). 

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 section 5.2). No adjustment of the 
starting dose is needed for patients with mild hepatic impairment (Child Pugh A) based on clinical 
data. 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 of 
nintedanib 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 impairment 
with Vargatef is not recommended (see sections 4.4 and 5.2). 

Method of administration
Vargatef capsules must be taken orally, preferably with food, swallowed whole with water, and must 
not be chewed or crushed. 



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4.3 Contraindications

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

4.4 Special warnings and precautions for use

Gastrointestinal disorders
Diarrhoea was the most frequently reported gastro-intestinal adverse reaction and appeared in close 
temporal 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 with 
nintedanib in the post-marketing period. Diarrhoea should be treated at first signs with adequate 
hydration and anti-diarrhoeal medicinal products, for example loperamide, and may require 
interruption, dose reduction or discontinuation of therapy with Vargatef (see section 4.2). 

Nausea and vomiting, mostly of mild to moderate severity, were frequently reported gastrointestinal 
adverse 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 for 
nausea 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 of 
electrolytes should be monitored, if relevant gastrointestinal adverse events occur. Interruption, dose 
reduction 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 fatal 
cases).

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 
Based on increased exposure, the risk for adverse events may be increased in patients with mild 
hepatic impairment (Child Pugh A; see sections 4.2 and 5.2). Limited safety data are available in 
9 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 to 
support a recommendation for treatment of patients with moderate hepatic impairment. The efficacy of 
nintedanib 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 severe 
hepatic impairment (Child Pugh C). Treatment with Vargatef is not recommended in patients with 
moderate or severe hepatic impairment (see section 4.2). 

Cases of drug-induced liver injury have been observed with nintedanib treatment, including severe
liver injury with fatal outcome. Elevation 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 initiation of the combination 
treatment with Vargatef plus docetaxel. The values should be monitored as clinically indicated or 



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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 section 4.2). 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; total 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 section 4.2).

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 section 5.2). Close monitoring is recommended 
in patients with these risk factors.

Renal function 
Cases of renal impairment/failure, in some cases with fatal outcome, have been reported with 
nintedanib use (see section 4.8).
Patients should be monitored during nintedanib therapy, with particular attention to those patients 
exhibiting risk factors for renal impairment/failure. In case of renal impairment/failure, therapy 
adjustment should be considered (see section 4.2 Dose adjustments).

Haemorrhage
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 was 
comparable (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 of 
respiratory 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 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.

Non-serious and serious bleeding events, some of which were fatal, have been reported in the post-
marketing period, including patients with or without anticoagulant therapy or other medicinal products
that could cause bleeding (for clinical trials’ data, see also ‘Therapeutic anticoagulation’ below). In 
case of bleeding, dose adjustment, interruption or discontinuation should be considered based on 
clinical judgement (see section 4.2). Post-marketing bleeding events include but are not limited to 
gastrointestinal, respiratory and central nervous system organs, with the most frequent being 
respiratory.

Therapeutic anticoagulation
There are no data available from clinical trials for patients with inherited predisposition to bleeding or 
for 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 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, international normalised ratio (INR), 
and clinical bleeding episodes.



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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.

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

Arterial thromboembolic events 
The frequency of arterial thromboembolic events was comparable between the two treatment arms in 
the phase 3 trial 1199.13 (LUME-Lung 1). Patients with a recent history of myocardial infarction or 
stroke were excluded from this trial. 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.

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

Gastrointestinal perforations 
The frequency of gastrointestinal perforation was comparable between the treatment arms in the 
clinical trial. However, based on the mechanism of action patients treated with Vargatef may have an 
increased risk of gastrointestinal perforations. Cases of gastrointestinal perforations, some of which 
were fatal, have been reported in the post-marketing period. Particular caution should be exercised 
when treating patients with previous abdominal surgery or a recent history of a hollow organ 
perforation. Vargatef should therefore only be initiated at least 4 weeks after major 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 LUME-Lung 1 trial. No dedicated trials 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.

Effect on QT interval
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 be 
exercised when administering nintedanib in patients who may develop QTc prolongation.



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

Special populations
In trial 1199.13 (LUME-Lung 1), there was a higher frequency of SAEs 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.

4.5 Interaction with other medicinal products and other forms of interaction

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 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 nintedanib, potent P-gp inhibitors (e.g. ketoconazole or erythromycin) may 
increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of 
nintedanib. Management of adverse reactions may require interruption, dose reduction, or 
discontinuation of therapy with Vargatef (see section 4.2).

Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decrease 
exposure 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. 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 section 5.2). The likelihood of drug-drug
interactions 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 either 
medicinal product to a relevant extent.
The potential for interactions of nintedanib with hormonal contraceptives was not explored.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception
Nintedanib may cause foetal harm in humans (see section 5.3). Women of childbearing potential being 
treated with Vargatef should be advised to avoid becoming pregnant while receiving this treatment and 
to use adequate contraception during and at least 3 months after the last dose of Vargatef. Since the 
effect of nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier 
methods should be applied as a second form of contraception, to avoid pregnancy.

Pregnancy
There is no information on the use of Vargatef in pregnant women, but preclinical studies in animals 
have shown reproductive toxicity of this active substance (see section 5.3). As nintedanib may cause 
foetal harm also in humans, it should not be used during pregnancy unless the clinical condition 
requires 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 during 
therapy with Vargatef. 



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

Breast-feeding
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 the 
administered dose) were secreted into milk of lactating rats. A risk to the breast-fed child cannot be 
excluded. Breast-feeding should be discontinued during treatment with Vargatef. 

Fertility
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 female 
fertility available.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile
The safety data provided in the sections below 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 drug reactions (ADRs) specific for nintedanib were diarrhoea, increased 
liver enzyme values (ALT and AST) and vomiting. Table 3 provides a summary of the adverse 
reactions by System Organ Class (SOC). For the management of selected adverse reactions, see
section 4.4. Information about selected adverse reactions observed from the LUME-Lung 1 trial are 
described below. 

Tabulated list of adverse reactions
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 the
post-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.



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Table 3: Summary of ADRs per frequency category 

System Organ 
Class

Very common 
(≥ 1/10)

Common 
(≥ 1/100 < 1/10)

Uncommon 
(≥ 1/1,000 < 1/100)

Not known

Infections and
infestations

Febrile neutropenia, 
Abscesses,

Sepsis

Blood and 
lymphatic system 

disorders

Neutropenia

(includes febrile 
neutropenia)

Thrombocytopenia

Metabolism and 
nutrition 
disorders

Decreased 
appetite, 

Electrolyte 
imbalance

Dehydration,

Weight decreased

Nervous system 
disorders

Peripheral 
neuropathy

Headache1)

Cardiac disorders Myocardial 
infarction (see 

section 4.4) 

Vascular 
disorders

Bleeding1)

(see section 4.4)

Venous 
thromboembolism3),

Hypertension

Aneurysms 
and artery 
dissections

Gastrointestinal 
disorders

Diarrhoea,

Vomiting,

Nausea,

Abdominal pain 

Perforation1)

Pancreatitis2)
Colitis

Hepatobiliary 
disorders

Alanine 
aminotransferase

(ALT)
increased,

Aspartate 
aminotransferase
(AST) increased,

Blood alkaline 
phosphatase

(ALKP)
increased

Hyperbilirubinaemia,

Gamma-
glutamyltransferase

(GGT) increased

Drug-induced liver 
injury

Skin and 
subcutaneous 

tissue disorders

Mucositis 
(including 
stomatitis),

Rash,

Alopecia1)

Pruritus

Renal and urinary 
disorders

Renal failure 

(see section 4.4)
1) In clinical trials the frequency was not increased in patients treated with nintedanib plus docetaxel as 

compared 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.



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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 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 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 sections 4.4 and 4.2, 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 section 4.4). 

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 medicinal products 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 
section 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
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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

There is no specific antidote or treatment for nintedanib overdose. The highest single dose of 
nintedanib administered in phase I studies was 450 mg once daily. In addition, 2 patients 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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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symptoms. Both patients recovered from these adverse reactions. In case of overdose, treatment should 
be interrupted and general supportive measures initiated as appropriate.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE31

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.

Pharmacodynamic 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 efficacy and safety
Efficacy in the pivotal phase 3 trial LUME-Lung 1
The efficacy and safety of Vargatef was investigated in 1314 adult patients with locally advanced, 
metastatic or recurrent NSCLC after one prior line of chemotherapy. `Locally recurrent´ was defined 
as 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, 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 intravenous 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 versus 1), bevacizumab 
pretreatment (yes versus no), brain metastasis (yes versus no) and tumour histology (squamous versus
non-squamous tumour histology).

Patient characteristics were balanced between treatment arms within the overall population and within
subgroups according to histology. 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



13

performance status was 0 (28.6 %) or 1 (71.3 %); one patient had a baseline ECOG performance status 
of 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 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 trial 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 trial with locally recurrent disease stage as had been 
evaluated at baseline.

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.

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 (hazard ratio (HR) 0.79; 95 % confidence 
interval (CI): 0.68 - 0.92; p = 0.0019) as determined by the Independent Review Committee. 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 (Table 4).

As shown in Table 4, 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 trial endpoints such as disease control and 
change in tumour size showed significant improvements.



14

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

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 -0.97
  p-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 
     the overall ITT population (332 events in adenocarcinoma patients). 
** Stratified by baseline ECOG PS (0 versus 1), brain metastases at baseline (yes versus no) and prior 

treatment with bevacizumab (yes versus no).
*** OS analysis and follow-up PFS-analysis performed when 1121 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 for baseline ECOG PS (0 versus 1), brain metastases at baseline (yes versus no) and prior 
treatment with bevacizumab (yes versus no). 

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 versus 12.6 months,
Figure 1).



15

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

A pre-specified evaluation was performed in the population of adenocarcinoma patients considered to 
have entered the trial with a particularly poor treatment prognosis, namely, patients who progressed 
during or shortly after first-line therapy prior to trial entry. This population included those 
adenocarcinoma patients identified at baseline as having progressed and entered the trial 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 trial ≥ 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 trial comparing nintedanib 
monotherapy against sunitinib monotherapy in patients with renal cell carcinoma. In this trial single 
oral doses of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administered 

No. of patients at risk

Placebo

Nintedanib

52.7 %

44.7 %

25.7 %

19.1 %

Time (months)

Median (months)

P
ro

b
ab

il
it

y 
o

f 
su

rv
iv

al
 (

%
)



16

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 population
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 for 
information on paediatric use).

5.2 Pharmacokinetic properties

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 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.

Biotransformation
The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free 
acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely 
UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. 

Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways with CYP 3A4 
being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected 
in plasma in the human ADME study. In vitro, CYP-dependent metabolism accounted for about 5 % 
compared to about 25 % ester cleavage.
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 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 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 %).

Linearity/non-linearity
The pharmacokinetics 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 



17

for Cmax and 1.38-fold for AUCτ. Nintedanib trough concentrations remained stable for more than one 
year.

Other information on drug-drug interactions

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 in preclinical studies 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 
section 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 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.

Pharmacokinetic/pharmacodynamic relationship(s)
In exploratory pharmacokinetic 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.

Population pharmocokinetic analysis in special populations
The pharmacokinetic properties of nintedanib were similar in healthy volunteers, cancer patients, and 
patients of the target population. Exposure to nintedanib was not influenced by gender (body weight 
corrected), 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, body 
weight, and race (see below). Based on the high inter-individual variability of exposure observed in 
the clinical LUME-Lung-1 trial these effects are not considered clinically relevant. However, close 
monitoring is recommended in patients with several of these risk factors (see section 4.4).

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 were 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 (5

th 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). Based on the high inter-individual variability of exposure these 
effects are not considered clinically relevant. Data from black individuals was very limited but in the 
same range as for Caucasians. 



18

Hepatic impairment
In a dedicated single dose phase I trial 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.

5.3 Preclinical safety data

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 to implantation in rats did not reveal 
effects on the male reproductive tract and male fertility. 

In rats, embryofoetal lethality and teratogenic effects were observed at exposure levels below human 
exposure, at the maximum recommended human dose (MRHD) of 200 mg b.i.d. 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 was observed at an exposure approximately 8 times higher than at 
the MRHD. Teratogenic effects on the aortic arches in combination with the heart and the urogenital 
system were noted at an exposure 4 times higher than at the MRHD and on the embryofoetal 
development 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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content  
Triglycerides, medium-chain
Hard fat
Soya lecithin (E322)

Capsule shell
Gelatin
Glycerol (85 %)
Titanium dioxide (E171)



19

Iron oxide red (E172)
Iron oxide yellow (E172)

Printing ink
Shellac 
Iron oxide black (E172)
Propylene glycol (E1520)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

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

6.5 Nature and contents of container 

Aluminium/aluminium blisters containing 10 capsules each.

Vargatef 100 mg soft capsules
Pack-sizes: 60 or 120 capsules, or multipack of 120 (2 x 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.

6.6 Special precautions for disposal 

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

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S)

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



20

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 November 2014
Date of latest renewal: 26 August 2019

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu

http://www.ema.europa.eu


21

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



22

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
55216 Ingelheim am Rhein
GERMANY

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 Periodic safety update reports 

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 Obligation to conduct post-authorisation measures 

The MAH shall complete, within the stated timeframe, the below measures:



23

Description Due date

In order to investigate suitable bio-/tumour markers (including VEGF) to allow 
identification and selection of a more targeted population of patients most likely 
to benefit from the treatment of nintedanib, the Applicant will conduct and submit 
results from a Biomarkers research programme including:
1. Collected blood samples from the LUME-Lung 1 and LUME-Lung 2 studies 

will be assessed for germline genetic variability in angiogenic factors, 
including VEGF or its downstream receptors. 

2. Single arm study to examine whether genetic/genomic markers (alone or 
combined with clinical covariates) could be used to predict overall survival 
(OS) in NSCLC patients eligible for treatment with nintedanib.

3. Data on bio-/tumour markers from all clinical studies in the clinical program 
for nintedanib. 
The applicant will implement collection of material for biomarker 
investigation and analyses of biomarker data into the study protocol of all 
new oncology studies planned for nintedanib in the future, wherever clinically 
appropriate.

Results will be 
provided on a 
yearly basis. 

Submission of 
final study
report of the 
single-arm 
study: Q4 2020



24

ANNEX III

LABELLING AND PACKAGE LEAFLET



25

A. LABELLING



26

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (100 mg)   

1. NAME OF THE MEDICINAL PRODUCT

Vargatef 100 mg soft capsules  
nintedanib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each capsule contains 100 mg nintedanib (as esilate).

3. LIST OF EXCIPIENTS

Contains soya. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

60 x 1 soft capsule
120 x 1 soft capsule

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



27

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH 
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/14/954/001
EU/1/14/954/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Vargatef 100 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



28

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (100 mg - 60 capsules for multipack  -  without Blue Box)

1. NAME OF THE MEDICINAL PRODUCT

Vargatef 100 mg soft capsules  
nintedanib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each capsule contains 100 mg nintedanib (as esilate).

3. LIST OF EXCIPIENTS

Contains soya. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

60 x 1 soft capsule. Component of a multipack, cannot be sold separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



29

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH 
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/14/954/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Vargatef 100 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



30

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER WRAPPER (100 mg – multipack of 120 capsules – contains Blue Box)

1. NAME OF THE MEDICINAL PRODUCT

Vargatef 100 mg soft capsules  
nintedanib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each capsule contains 100 mg nintedanib (as esilate).

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Multipack: 120 (2 packs of 60 x1) soft capsules. 

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



31

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH 
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/14/954/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Vargatef 100 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



32

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (150 mg)  

1. NAME OF THE MEDICINAL PRODUCT

Vargatef 150 mg soft capsules  
nintedanib

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each capsule contains 150 mg nintedanib (as esilate).

3. LIST OF EXCIPIENTS

Contains soya. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

60 x 1 soft capsule

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

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



33

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH 
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/14/954/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Vargatef 150 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



34

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER (100 mg)  

1. NAME OF THE MEDICINAL PRODUCT

Vargatef 100 mg capsules
Nintedanib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Do not open before use.



35

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER (150 mg) 

1. NAME OF THE MEDICINAL PRODUCT

Vargatef 150 mg capsules
Nintedanib

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Do not open before use.



36

B. PACKAGE LEAFLET



37

Package leaflet: Information for the patient

Vargatef 100 mg soft capsules
nintedanib

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Vargatef is and what it is used for 
2. What you need to know before you take Vargatef 
3. How to take Vargatef 
4. Possible side effects 
5. How to store Vargatef 
6. Contents of the pack and other information

1. What Vargatef is and what it is used for

Vargatef capsules contain the active substance nintedanib. Nintedanib blocks the activity of a group of 
proteins which are involved in the development of new blood vessels that cancer cells need to supply 
them with food and oxygen. By blocking the activity of these proteins, nintedanib can help stop the 
growth and spread of the cancer.

This medicine is used in combination with another cancer medicine (docetaxel) to treat a cancer of the 
lung called non-small cell lung cancer (NSCLC). It is for adult patients whose NSCLC is of a certain 
type (“adenocarcinoma”) and who had already received one treatment with another medicine to treat 
this cancer but whose tumour started to grow again.

2. What you need to know before you take Vargatef

Do not take Vargatef
- if you are allergic to nintedanib, to peanut or soya, or to any of the other ingredients of this 

medicine (listed in section 6)

Warnings and precautions 
Talk to your doctor or pharmacist before taking this medicine
- if you have or had liver problems, if you have or had bleeding problems, particularly recent 

bleeding in the lung 
- if you have or ever had problems with your kidney
- if you take blood-thinning medicines (such as warfarin, phenprocoumon, heparin or 

acetylsalicylic acid) to prevent blood clotting. Treatment with Vargatef may lead to a higher risk 
of bleeding

- if you have recently had a surgery or plan to have a surgery. Nintedanib may affect the way 
your wounds heal. Therefore treatment with Vargatef will usually be interrupted if you are 
having surgery. Your doctor will decide when to resume your treatment with this medicine

- if you have cancer that has spread to the brain



38

- if you have high blood pressure
- if you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a 

tear in a blood vessel wall

Based on this information your doctor may carry out some blood tests, for example to check your liver 
function and to determine how fast your blood can clot. Your doctor will discuss the results of these 
tests with you and decide whether you can be given Vargatef.

Inform your doctor immediately while taking this medicine
- if you get diarrhoea. Treatment of diarrhoea at the first signs is important (see section 4)
- if you vomit or feel sick (nausea)
- if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes 

(jaundice), dark or brown (tea coloured) urine, pain on the upper right side of your stomach area 
(abdomen), bleeding or bruising more easily than normal, or feeling tired. This could be 
symptoms of serious liver problems

- if you develop fever, chills, fast breathing or a fast heartbeat. These could be signs of infection 
or infection of the blood (sepsis) (see section 4)

- if you experience severe pain in your stomach area, fever, chills, sickness, vomiting, or 
abdominal rigidity or bloating, as these could be symptoms of a hole in the wall of your gut 
(‘gastrointestinal perforation’)

- if you experience pain, swelling, reddening, warmth of a limb or if you experience chest pain 
and difficulty to breathe as these could be symptoms of a blood clot in one of your veins

- if you have any major bleeding
- if you experience chest pressure or pain, typically on the left side of the body, pain in the neck, 

jaw, shoulder or arm, a fast heartbeat, shortness of breath, nausea, vomiting, as this could be 
symptoms of a heart attack

- if any side effect(s) you may get (see section 4) becomes serious

Children and adolescents
This medicine has not been studied in children or adolescents and is therefore not to be taken by 
children and adolescents below the age of 18 years.

Other medicines and Vargatef 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including herbal medicines and medicines obtained without a prescription.

This medicine can interact with certain other medicines. The following medicines may increase the 
blood levels of nintedanib, the active substance of Vargatef, and hence may increase the risk for side 
effects (see section 4):
- Ketoconazole (used to treat fungal infections)
- Erythromycin (used to treat bacterial infections)
The following medicines may decrease the blood levels of nintedanib and thus may lead to reduction 
of the effectiveness of Vargatef:
- Rifampicin (an antibiotic used to treat tuberculosis)
- Carbamazepine, phenytoin (used to treat seizures)
- St. John’s Wort (a herbal medicine to treat depression)

Pregnancy 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.

Do not take this medicine during pregnancy, as it can harm your unborn baby and cause birth defects. 
Women who can become pregnant must use an effective combination of birth control methods, 
including barrier methods as a second form of contraception, while they are taking Vargatef and for at 
least 3 months after stopping treatment. You should discuss the most appropriate methods of 
contraception for you with your doctor.



39

Tell your doctor or pharmacist immediately if you become pregnant during treatment with Vargatef.

Breast-feeding
It is not known if the medicine passes into breast milk and could cause harm to a breast-fed child. 
Therefore, women should not breast-feed during treatment with Vargatef.

Fertility 
The effect of this medicine on human fertility has not been investigated. 

Driving and using machines
Vargatef may have minor influence on your ability to drive and use machines. You should not drive or 
use machines if you feel sick.

Vargatef contains soya
The capsules contain soya lecithin. If you are allergic to peanut or soya, do not use this medicine.

3. How to take Vargatef

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist  if you are not sure.

Do not take Vargatef on the same day as your chemotherapy treatment with docetaxel.

Swallow the capsules whole with water and do not chew or crush them. It is recommended to take the 
capsules with food, i.e. during or immediately before or after a meal. 

The recommended dose is four capsules per day (this is a total of 400 mg nintedanib per day). Do not 
take more than this dose.

This daily dose should be split into two doses of two capsules about 12 hours apart, for example two 
capsules in the morning and two capsules in the evening. These two doses should be taken at around 
the same time each day. Taking the medicine this way ensures that a steady amount of nintedanib is 
maintained in the body.

Dose reduction
If you cannot tolerate the recommended dose of 400 mg per day because of side effects (see section 4),
your doctor may reduce the daily dose of Vargatef. Do not reduce the dose or stop the treatment 
yourself without consulting your doctor first.

Your doctor may reduce your recommended dose to 300 mg per day (two capsules of 150 mg). In this 
case your doctor will prescribe Vargatef 150 mg soft capsules for your treatment. 

If necessary, your doctor may further reduce your daily dose to 200 mg per day (two capsules of 100 
mg). You will be prescribed the appropriate capsule strength by your doctor if this happens. 

In both cases, you should take one capsule of the appropriate strength twice daily approximately 
12 hours apart with food (for example in the morning and in the evening) at about the same time of the 
day. 

In case your doctor has stopped your chemotherapy with docetaxel you should continue to take 
Vargatef twice daily.

If you take more Vargatef than you should
Contact your doctor or pharmacist immediately.



40

If you forget to take Vargatef
Do not take a double dose to make up for a forgotten dose. Take your next dose of Vargatef as planned 
at the next scheduled time and at the dose recommended by your doctor or pharmacist.

If you stop taking Vargatef 
Do not stop taking Vargatef without consulting your doctor first. It is important to take this medicine 
every day, as long as your doctor prescribes it for you. If you do not take this medicine as prescribed 
by your doctor, this cancer treatment may not work properly.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You need to pay special attention if you get the following side effects during treatment with Vargatef:

 Diarrhoea (very common, may affect more than 1 in 10 people)
Diarrhoea may lead to a loss of fluid and important salts (electrolytes, such as sodium or potassium) in 
your body. At the first signs of diarrhoea drink plenty of fluids and contact your doctor immediately. 
Start appropriate anti-diarrhoeal treatment, e.g. with loperamide, as soon as possible after having 
contacted your doctor. 

 Febrile neutropenia and sepsis (common, may affect up to 1 in 10 people)
Treatment with Vargatef may lead to a reduced number of a type of your white blood cells 
(neutropenia) which are important for the body´s reaction against bacterial or fungal infections. As a 
consequence of neutropenia, fever (febrile neutropenia) and blood infection (sepsis) may occur. Tell 
your doctor immediately if you develop fever, chills, fast breathing or a fast heartbeat.
During treatment with Vargatef your doctor will regularly monitor your blood cells and examine you 
for signs of infection, such as inflammation, fever or tiredness.

The following side effects were observed under treatment with this medicine:

Very common side effects (may affect more than 1 in 10 people)
 Diarrhoea – please see above 
 Painful, numb and/or tingling feeling in fingers and toes (peripheral neuropathy)
 Feeling sick (nausea)
 Throwing up (vomiting)
 Pain in the stomach (abdomen) 
 Bleeding
 Decrease in the number of white blood cells (neutropenia)
 Inflammation of the mucous membranes lining the digestive tract including sores and ulcers in 

the mouth (mucositis, including stomatitis)
 Rash 
 Decreased appetite
 Electrolyte imbalance
 Increased liver enzyme values (alanine aminotransferase, aspartate aminotransferase, blood 

alkaline phosphatase) in the blood as seen from blood tests
 Hair loss (alopecia)

Common side effects (may affect up to 1 in 10 people)
 Blood poisoning (sepsis) - please see above
 Decrease in the number of white blood cells accompanied by fever (febrile neutropenia)
 Blood clots in the veins (venous thromboembolism), especially in the legs (symptoms include 

pain, redness, swelling, and warmth of a limb), which may travel through blood vessels to the 



41

lungs causing chest pain and difficulty in breathing (if you notice any of these symptoms, seek 
medical advice immediately)

 High blood pressure (hypertension)
 Fluid loss (dehydration)
 Abscesses
 Low platelet count (thrombocytopenia)
 Jaundice (hyperbilirubinaemia)
 Increased liver enzyme values (gamma-glutamyltransferase) in the blood as seen from blood 

tests
 Weight loss
 Itching
 Headache

Uncommon side effects (may affect up to 1 in 100 people)
 Occurrence of holes in the wall of your gut (gastrointestinal perforation)
 Serious liver problems
 Inflammation of the pancreas (pancreatitis)
 Myocardial infarction
 Renal failure

Not known (cannot be estimated from the available data)
 Inflammation of the large bowel
 An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall 

(aneurysms and artery dissections)

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Vargatef

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, wrapper and blisters. The 
expiry date refers to the last day of that month.

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

Do not use this medicine if you notice that the blister containing the capsules is opened or a capsule is 
broken.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Vargatef contains
The active substance is nintedanib. Each soft capsule contains 100 mg nintedanib (as esilate). 

The excipients are:
Capsule content: Triglycerides medium-chain, hard fat, soya lecithin (E322)

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


42

Capsule shell: Gelatin, glycerol (85 %), titanium dioxide (E171), iron oxide red (E172),
iron oxide yellow (E172)

Printing ink:   Shellac, iron oxide black (E172), propylene glycol (E1520)

What Vargatef looks like and contents of the pack
Vargatef 100 mg soft capsules (capsules) are peach-coloured, opaque, oblong capsules imprinted on 
one side in black with the Boehringer Ingelheim company symbol and the figure “100”.

Three pack-sizes of Vargatef 100 mg soft capsules are available:
 One box containing 60 capsules (6 aluminium blisters of 10 capsules each).
 One box containing 120 capsules (12 aluminium blisters of 10 capsules each).
 A multipack containing 120 capsules (2 boxes of 60 capsules each, bundled together by a 

wrapping foil).

Not all pack-sizes of Vargatef 100 mg soft capsules may be marketed.

Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany



43

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11 

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922 

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11 

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111 

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88 

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900 

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000 

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300 

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00 

Polska
Boehringer Ingelheim Sp. z o.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33 

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620 

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00



44

Ísland
Vistor hf.
Sími: +354 535 7000 

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011 

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600 

This leaflet was last revised in 

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

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


45

Package leaflet: Information for the patient

Vargatef 150 mg soft capsules
nintedanib

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Vargatef is and what it is used for 
2. What you need to know before you take Vargatef 
3. How to take Vargatef 
4. Possible side effects 
5. How to store Vargatef 
6. Contents of the pack and other information

1. What Vargatef is and what it is used for

Vargatef capsules contain the active substance nintedanib. Nintedanib blocks the activity of a group of 
proteins which are involved in the development of new blood vessels that cancer cells need to supply 
them with food and oxygen. By blocking the activity of these proteins, nintedanib can help stop the 
growth and spread of the cancer. 

This medicine is used in combination with another cancer medicine (docetaxel) to treat a cancer of the 
lung called non-small cell lung cancer (NSCLC). It is for adult patients whose NSCLC is of a certain 
type (“adenocarcinoma”) and who had already received one treatment with another medicine to treat 
this cancer but whose tumour started to grow again.

2. What you need to know before you take Vargatef

Do not take Vargatef
- if you are allergic to nintedanib, to peanut or soya, or to any of the other ingredients of this 

medicine (listed in section 6). 

Warnings and precautions 

Talk to your doctor or pharmacist before taking this medicine
- if you have or had liver problems, if you have or had bleeding problems, particularly recent 

bleeding in the lung 
- if you have or ever had problems with your kidney
- if you take blood-thinning medicines (such as warfarin, phenprocoumon, heparin or 

acetylsalicylic acid) to prevent blood clotting. Treatment with Vargatef may lead to a higher risk 
of bleeding

- if you have  recently had a surgery or plan to have a surgery. Nintedanib may affect the way 
your wounds heal. Therefore treatment with Vargatef will usually be interrupted if you are 
having surgery. Your doctor will decide when to resume your treatment with this medicine



46

- if you have cancer that has spread to the brain
- if you have high blood pressure
- if you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a 

tear in a blood vessel wall

Based on this information your doctor may carry out some blood tests, for example to check your liver 
function and to determine how fast your blood can clot. Your doctor will discuss the results of these 
tests with you and decide whether you can be given Vargatef.

Inform your doctor immediately while taking this medicine 
- if you get diarrhoea. Treatment of diarrhoea at the first signs is important (see section 4)
- if you vomit or feel sick (nausea)
- if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes 

(jaundice), dark or brown (tea coloured) urine, pain on the upper right side of your stomach area 
(abdomen), bleeding or bruising more easily than normal, or feeling tired. This could be 
symptoms of serious liver problems

- if you develop fever, chills, fast breathing or a fast heartbeat. These could be signs of infection 
or infection of the blood (sepsis) (see section 4)

- if you experience severe pain in your stomach area, fever, chills, sickness, vomiting, or 
abdominal rigidity or bloating, as these could be symptoms of a hole in the wall of your gut 
(‘gastrointestinal perforation’)

- if you experience pain, swelling, reddening, warmth of a limb or if you experience chest pain 
and difficulty to breathe as these could be symptoms of a blood clot in one of your veins

- if you have any major bleeding
- if you experience chest pressure or pain, typically on the left side of the body, pain in the neck, 

jaw, shoulder or arm, a fast heartbeat, shortness of breath, nausea, vomiting, as this could be 
symptoms of a heart attack

- if any side effect(s) you may get (see section 4) becomes serious

Children and adolescents
This medicine has not been studied in children or adolescents and is therefore not to be taken by 
children and adolescents below the age of 18 years.

Other medicines and Vargatef 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including herbal medicines and medicines obtained without a prescription.

This medicine can interact with certain other medicines. The following medicines may increase the 
blood levels of nintedanib, the active substance of Vargatef, and hence may increase the risk for side 
effects (see section 4):
- Ketoconazole (used to treat fungal infections)
- Erythromycin (used to treat bacterial infections)
The following medicines may decrease the blood levels of nintedanib and thus may lead to reduction 
of the effectiveness of Vargatef:
- Rifampicin (an antibiotic used to treat tuberculosis)
- Carbamazepine, phenytoin (used to treat seizures)
- St. John’s Wort (a herbal medicine to treat depression)

Pregnancy 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.

Do not take this medicine during pregnancy, as it can harm your unborn baby and cause birth defects. 
Women who can become pregnant must use an effective combination of birth control methods, 
including barrier methods as a second form of contraception, while they are taking Vargatef and for at 
least 3 months after stopping treatment. You should discuss the most appropriate methods of 



47

contraception for you with your doctor. Tell your doctor or pharmacist immediately if you become 
pregnant during treatment with Vargatef. 

Breast-feeding
It is not known if the medicine passes into breast milk and could cause harm to a breast-fed child. 
Therefore, women should not breast-feed during treatment with Vargatef. 

Fertility 
The effect of this medicine on human fertility has not been investigated. 

Driving and using machines
Vargatef may have minor influence on your ability to drive and use machines. You should not drive or 
use machines if you feel sick.

Vargatef contains soya
The capsules contain soya lecithin. If you are allergic to peanut or soya, do not use this medicine.

3. How to take Vargatef

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist  if you are not sure.

Do not take Vargatef on the same day as your chemotherapy treatment with docetaxel.

Swallow the capsules whole with water and do not chew or crush them. It is recommended to take the 
capsule with food, i.e. during or immediately before or after a meal. 

The recommended dose is two capsules per day (this is a total of 300 mg nintedanib per day). Do not 
take more than this dose.

This daily dose should be split into two doses of one capsule about 12 hours apart, for example one 
capsule in the morning and one capsule in the evening. The two doses should be taken at around the 
same time each day. Taking the medicine this way ensures that a steady amount of nintedanib is 
maintained in the body.

Dose reduction
If you cannot tolerate the recommended dose of 300 mg per day because of side effects (see section 4),
your doctor may reduce your recommended daily dose of Vargatef to 200 mg per day (two capsules of 
100 mg). In this case your doctor will prescribe Vargatef 100 mg soft capsules for your treatment. 
You should take one capsule of this strength twice daily approximately 12 hours apart with food (for 
example in the morning and in the evening) at about the same time of the day. 

Do not reduce the dose or stop the treatment yourself without consulting your doctor first.

In case your doctor has stopped your chemotherapy with docetaxel you should continue to take 
Vargatef twice daily.

If you take more Vargatef than you should
Contact your doctor or pharmacist immediately.

If you forget to take Vargatef
Do not take a double dose to make up for a forgotten dose. Take your next dose of Vargatef as planned 
at the next scheduled time and at the dose recommended by your doctor or pharmacist.



48

If you stop taking Vargatef 
Do not stop taking Vargatef without consulting your doctor first. It is important to take this medicine 
every day, as long as your doctor prescribes it for you. If you do not take this medicine as prescribed 
by your doctor, this cancer treatment may not work properly.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You need to pay special attention if you get the following side effects during treatment with Vargatef:

 Diarrhoea (very common, may affect more than 1 in 10 people)
Diarrhoea may lead to a loss of fluid and important salts (electrolytes, such as sodium or potassium) in 
your body. At the first signs of diarrhoea drink plenty of fluids and contact your doctor immediately. 
Start appropriate anti-diarrhoeal treatment, e.g. with loperamide, as soon as possible after having 
contacted your doctor. 

 Febrile neutropenia and sepsis (common, may affect up to 1 in 10 people)
Treatment with Vargatef may lead to a reduced number of a type of your white blood cells 
(neutropenia) which are important for the body´s reaction against bacterial or fungal infections. As a 
consequence of neutropenia, fever (febrile neutropenia) and blood infection (sepsis) may occur. Tell 
your doctor immediately if you develop fever, chills, fast breathing or a fast heartbeat.
During treatment with Vargatef your doctor will regularly monitor your blood cells and examine you 
for signs of infection, such as inflammation, fever or tiredness.

The following side effects were observed under treatment with this medicine:

Very common side effects (may affect more than 1 in 10 people)
 Diarrhoea – please see above 
 Painful, numb and/or tingling feeling in fingers and toes (peripheral neuropathy)
 Feeling sick (nausea)
 Throwing up (vomiting)
 Pain in the stomach (abdomen) 
 Bleeding
 Decrease in the number of white blood cells (neutropenia)
 Inflammation of the mucous membranes lining the digestive tract including sores and ulcers in 

the mouth (mucositis, including stomatitis)
 Rash 
 Decreased appetite
 Electrolyte imbalance
 Increased liver enzyme values (alanine aminotransferase, aspartate aminotransferase, blood 

alkaline phosphatase) in the blood as seen from blood tests
 Hair loss (alopecia)

Common side effects (may affect up to 1 in 10 people)
 Blood poisoning (sepsis) - please see above
 Decrease in the number of white blood cells accompanied by fever (febrile neutropenia)
 Blood clots in the veins (venous thromboembolism), especially in the legs (symptoms include 

pain, redness, swelling, and warmth of a limb), which may travel through blood vessels to the 
lungs causing chest pain and difficulty in breathing (if you notice any of these symptoms, seek 
medical advice immediately)

 High blood pressure (hypertension)
 Fluid loss (dehydration)



49

 Abscesses
 Low platelet count (thrombocytopenia)
 Jaundice (hyperbilirubinaemia)
 Increased liver enzyme values (gamma-glutamyltransferase) in the blood as seen from blood 

tests
 Weight loss
 Itching
 Headache

Uncommon side effects (may affect up to 1 in 100 people)
 Occurrence of holes in the wall of your gut (gastrointestinal perforation)
 Serious liver problems
 Inflammation of the pancreas (pancreatitis)
 Myocardial infarction
 Renal failure

Not known (cannot be estimated from the available data)
 Inflammation of the large bowel
 An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall 

(aneurysms and artery dissections)

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Vargatef

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blisters. The expiry 
date refers to the last day of that month.

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

Do not use this medicine if you notice that the blister containing the capsules is opened or a capsule is 
broken.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Vargatef contains
The active substance is nintedanib. Each soft capsule contains 150 mg nintedanib (as esilate). 

The excipients are:
Capsule content: Triglycerides medium-chain, hard fat, soya lecithin (E322)
Capsule shell: Gelatin, glycerol (85 %), titanium dioxide (E171), iron oxide red (E172), 

iron oxide yellow (E172)
Black ink: Shellac, iron oxide black (E172), propylene glycol (E1520)

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


50

What Vargatef looks like and contents of the pack
Vargatef 150 mg soft capsules (capsules) are brown-coloured, opaque, oblong capsules imprinted on 
one side in black with the Boehringer Ingelheim company symbol and the figure “150”.

One box contains 60 capsules (6 aluminium blisters of 10 capsules each).

Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany



51

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11 

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922 

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11 

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111 

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 8900

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88 

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900 

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000 

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300 

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-7870

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00 

Polska
Boehringer Ingelheim Sp. z o.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33 

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620 

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00



52

Ísland
Vistor hf.
Sími: +354 535 7000 

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011 

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600 

This leaflet was last revised in 

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.

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


53

Annex IV

Scientific conclusions and grounds for the variation to the terms of the marketing 
authorisation(s)



54

Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for nintedanib (oncology 

indications), the scientific conclusions of CHMP are as follows: 

The MAH presented data from all sources regarding ‘Sepsis’, reported cumulatively and during the 

interval. Sepsis is listed in the Product Information as a common adverse reaction, and there is also a 

warning in the relevant sections of the Product Information for neutropenia and sepsis. The MAH 

analysed the data from 17 fatal cases of sepsis reported cumulatively in the post -marketing period. 

These fatal cases are approximately 1/3 of the 50 cases of sepsis reported cumulatively. Four (4) fatal 

cases were reported in the interval. There was no consistent pattern identified regarding the aetiology 

for the sepsis events cumulatively or in the interval. However, in two of the cases reported in the 

interval no other factor could be found besides the administration of the combination of Nintedanib 

and Docetaxel. In both cases, the reporter had considered that there was a reasonable possibility for a 

causal role of Vargatef. 

The PRAC considers that the role of Vargatef cannot be discarded in the cumulative or interval fatal 

cases, as sepsis is a common adverse reaction and vargatef is co -administered with docetaxel. The 

product information is updated to inform about the fatal cases of sepsis and warn patients about early 

detection of signs of sepsis.

The CHMP agrees with the scientific conclusions made by the PRAC.

Grounds for the variation to the terms of the marketing authorisation(s)

On the basis of the scientific conclusions for nintedanib (oncology indications) the CHMP is of the 

opinion that the benefit-risk balance of the medicinal product(s) containing nintedanib (oncology 

indications) is unchanged subject to the proposed changes to the product information.

The CHMP recommends that the terms of the marketing authorisation(s) should be varied.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A.	MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B.	CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.	OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D.	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)