Ofev

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Ofev 100 mg soft capsules
Ofev 150 mg soft capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Soft capsule (capsule).

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

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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

Ofev is also indicated in adults for the treatment of other chronic fibrosing interstitial lung diseases 
(ILDs) with a progressive phenotype (see section 5.1).

Ofev is indicated in adults for the treatment of systemic sclerosis associated interstitial lung disease 
(SSc-ILD).

4.2 Posology and method of administration

Treatment should be initiated by physicians experienced in the management of diseases for which 
Ofev is approved.

Posology
The recommended dose is 150 mg nintedanib twice daily administered approximately 12 hours apart.
The 100 mg twice daily dose is only recommended to be used in patients who do not tolerate the 
150 mg twice daily dose.



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If a dose is missed, administration should resume at the next scheduled time at the recommended dose.
If a dose is missed the patient should not take an additional dose. The recommended maximum daily 
dose of 300 mg should not be exceeded.

Dose adjustments
In addition to symptomatic treatment if applicable, the management of adverse reactions to Ofev (see 
sections 4.4 and 4.8) could include dose reduction and temporary interruption until the specific 
adverse reaction has resolved to levels that allow continuation of therapy. Ofev treatment may be 
resumed at the full dose (150 mg twice daily) or a reduced dose (100 mg twice daily). If a patient does 
not tolerate 100 mg twice daily, treatment with Ofev should be discontinued.

If diarrhoea, nausea and/or vomiting persist despite appropriate supportive care (including anti-emetic 
therapy), dose reduction or treatment interruption may be required. The treatment may be resumed at a 
reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe 
diarrhoea, nausea and/or vomiting despite symptomatic treatment, therapy with Ofev should be 
discontinued (see section 4.4).

In case of interruptions due to aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
elevations > 3x upper limit of normal (ULN), once transaminases have returned to baseline values,
treatment with Ofev may be reintroduced at a reduced dose (100 mg twice daily) which subsequently 
may be increased to the full dose (150 mg twice daily) (see sections 4.4 and 4.8).

Special populations
Elderly patients (≥ 65 years)
No overall differences in safety and efficacy were observed for elderly patients. No a-priori dose 
adjustment is required on the basis of a patient’s age. Patients ≥75 years may be more likely to require 
dose reduction to manage adverse effects (see section 5.2).

Renal impairment
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
In patients with mild hepatic impairment (Child Pugh A), the recommended dose of Ofev is 100 mg 
twice daily approximately 12 hours apart. In patients with mild hepatic impairment (Child Pugh A), 
treatment interruption or discontinuation for management of adverse reactions should be considered.
The safety and efficacy of nintedanib have not been investigated in patients with hepatic impairment 
classified as Child Pugh B and C. Treatment of patients with moderate (Child Pugh B) and severe 
(Child Pugh C) hepatic impairment with Ofev is not recommended (see section 5.2).

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

Method of administration 
Ofev is for oral use. The capsules should be taken with food, swallowed whole with water, and should 
not be chewed or crushed.

4.3 Contraindications

 Pregnancy (see section 4.6)
 Hypersensitivity to nintedanib, to peanut or soya, or to any of the excipients listed in section 6.1.



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4.4 Special warnings and precautions for use

Gastrointestinal disorders
Diarrhoea
In the clinical trials (see section 5.1), diarrhoea was the most frequent gastro-intestinal adverse 
reaction reported (see section 4.8). In most patients, the adverse reaction was of mild to moderate 
intensity and occurred within the first 3 months of treatment.

Serious cases of diarrhoea leading to dehydration and electrolyte disturbances have been reported in 
the post-marketing. Patients should be treated at first signs with adequate hydration and anti-diarrhoeal 
medicinal products, e.g. loperamide, and may require dose reduction or treatment interruption. Ofev
treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice 
daily). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with Ofev should 
be discontinued.

Nausea and vomiting
Nausea and vomiting were frequently reported gastrointestinal adverse reactions (see section 4.8). In 
most patients with nausea and vomiting, the event was of mild to moderate intensity. In clinical trials, 
nausea led to discontinuation of Ofev in up to 2.1% of patients and vomiting led to discontinuation of 
Ofev in up to 1.4% of patients.

If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction 
or treatment interruption may be required. The treatment may be resumed at a reduced dose (100 mg 
twice daily) or at the full dose (150 mg twice daily). In case of persisting severe symptoms therapy 
with Ofev should be discontinued.

Hepatic function 
The safety and efficacy of Ofev has not been studied in patients with moderate (Child Pugh B) or 
severe (Child Pugh C) hepatic impairment. Therefore, treatment with Ofev is not recommended in 
such patients (see section 4.2). Based on increased exposure, the risk for adverse reactions may be 
increased in patients with mild hepatic impairment (Child Pugh A). Patients with mild hepatic 
impairment (Child Pugh A) should be treated with a reduced dose of Ofev (see sections 4.2 and 5.2).

Cases of drug-induced liver injury have been observed with nintedanib treatment, including severe 
liver injury with fatal outcome. The majority of hepatic events occur within the first three months of 
treatment. Therefore, hepatic transaminase and bilirubin levels should be investigated before treatment
initiation and during the first month of treatment with Ofev. Patients should then be monitored at 
regular intervals during the subsequent two months of treatment and periodically thereafter, e.g. at 
each patient visit or as clinically indicated.

Elevations of liver enzymes (ALT, AST, blood alkaline phosphatase (ALKP), gamma-glutamyl-
transferase (GGT), see section 4.8) and bilirubin were reversible upon dose reduction or interruption in 
the majority of cases. If transaminase (AST or ALT) elevations > 3x ULN are measured, dose 
reduction or interruption of the therapy with Ofev is recommended and the patient should be 
monitored closely. Once transaminases have returned to baseline values, treatment with Ofev may be 
resumed at the full dose (150 mg twice daily) or reintroduced at a reduced dose (100 mg twice daily) 
which subsequently may be increased to the full dose (see section 4.2). If any liver test elevations are 
associated with clinical signs or symptoms of liver injury, e.g. jaundice, treatment with Ofev should be 
permanently discontinued. Alternative causes of the liver enzyme elevations should be investigated. 

Patients with low body weight (< 65 kg), Asian and female patients have a higher risk of elevations of 
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.



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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
Vascular endothelial growth factor receptor (VEGFR) inhibition might be associated with an increased 
risk of bleeding.
Patients at known risk for bleeding including patients with inherited predisposition to bleeding or 
patients receiving a full dose of anticoagulative treatment were not included in the clinical trials. 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). Therefore, these patients should only be treated with Ofev if the anticipated 
benefit outweighs the potential risk.

Arterial thromboembolic events
Patients with a recent history of myocardial infarction or stroke were excluded from the clinical trials.
In the clinical trials, arterial thromboembolic events were infrequently reported (Ofev 2.5% versus 
placebo 0.7% for INPULSIS; Ofev 0.9% versus placebo 0.9% for INBUILD; Ofev 0.7% versus 
placebo 0.7% for SENSCIS). In the INPULSIS trials, a higher percentage of patients experienced 
myocardial infarctions in the Ofev group (1.6%) compared to the placebo group (0.5%), while adverse 
events reflecting ischaemic heart disease were balanced between the Ofev and placebo groups. In the 
INBUILD trial, myocardial infarction was observed with low frequency: Ofev 0.9% versus placebo 
0.9%. In the SENSCIS trial, myocardial infarction was observed with low frequency in the placebo 
group (0.7%) and not observed in the Ofev group. Caution should be used when treating patients at 
higher cardiovascular risk including known coronary artery disease. Treatment interruption should be 
considered in patients who develop signs or symptoms of acute myocardial ischemia.

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 Ofev, this risk should be carefully 
considered in patients with risk factors such as hypertension or history of aneurysm.

Venous thromboembolism
In the clinical trials, no increased risk of venous thromboembolism was observed in nintedanib treated 
patients. Due to the mechanism of action of nintedanib patients might have an increased risk of 
thromboembolic events.

Gastrointestinal perforations and ischaemic colitis
In the clinical trials, the frequency of patients with perforation was up to 0.3% in both treatment 
groups. Due to the mechanism of action of nintedanib, patients might have an increased risk of 
gastrointestinal perforations. Cases of gastrointestinal perforations and cases of ischaemic colitis, 
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, previous history of peptic 
ulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs. Ofev should only 
be initiated at least 4 weeks after abdominal surgery. Therapy with Ofev should be permanently 
discontinued in patients who develop gastrointestinal perforation or ischaemic colitis. Exceptionally, 
Ofev can be reintroduced after complete resolution of ischaemic colitis and careful assessment of 
patient’s condition and other risk factors.

Hypertension
Administration of Ofev may increase blood pressure. Systemic blood pressure should be measured 
periodically and as clinically indicated.



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Pulmonary hypertension
Data on the use of Ofev in patients with pulmonary hypertension is limited.
Patients with significant pulmonary hypertension (cardiac index ≤ 2 L/min/m², or parenteral 
epoprostenol/treprostinil, or significant right heart failure) were excluded from the INBUILD and 
SENSCIS trials.
Ofev should not be used in patients with severe pulmonary hypertension. Close monitoring is 
recommended in patients with mild to moderate pulmonary hypertension.

Wound healing complication
No increased frequency of impaired wound healing was observed in the clinical trials. Based on the 
mechanism of action nintedanib may impair wound healing. No dedicated studies investigating the 
effect of nintedanib on wound healing were performed. Treatment with Ofev should therefore only be 
initiated or - in case of perioperative interruption - resumed based on clinical judgement of adequate 
wound healing.

Co-administration with pirfenidone
In a dedicated pharmacokinetic study, concomitant treatment of nintedanib with pirfenidone was 
investigated in patients with IPF. Based on these results, there is no evidence of a relevant 
pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when administered in 
combination (see section 5.2). Given the similarity in safety profiles for both medicinal products, 
additive adverse reactions, including gastrointestinal and hepatic adverse events, may be expected.
The benefit-risk balance of concomitant treatment with pirfenidone has not been established.

Effect on QT interval
No evidence of QT prolongation was observed for nintedanib in the clinical trial programme 
(Section 5.1). As some other tyrosine kinase inhibitors are known to exert an effect on QT, caution 
should be exercised when nintedanib is administered in patients who may develop QTc prolongation.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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 Ofev, potent P-gp inhibitors (e.g. ketoconazole, erythromycin or cyclosporine) 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 Ofev (see section 4.2).

Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decrease 
exposure to nintedanib. Selection of an alternate concomitant medicinal product with no or minimal P-
gp induction potential should be 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.



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

Co-administration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib (see 
section 5.2).

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 
should be advised to avoid becoming pregnant while receiving treatment with Ofev and to use highly 
effective contraceptive methods at initiation of, during and at least 3 months after the last dose of 
Ofev. Nintedanib does not relevantly affect the plasma exposure of ethinylestradiol and levonorgestrel 
(see section 5.2). The efficacy of oral hormonal contraceptives may be compromised by vomiting 
and/or diarrhoea or other conditions where the absorption may be affected. Women taking oral 
hormonal contraceptives experiencing these conditions should be advised to use an alternative highly 
effective contraceptive measure.

Pregnancy
There is no information on the use of Ofev in pregnant women, but pre-clinical studies in animals have 
shown reproductive toxicity of this active substance (see section 5.3). As nintedanib may cause foetal 
harm also in humans, it must not be used during pregnancy (see section 4.3) and pregnancy testing 
must be conducted prior to treatment with Ofev and during treatment as appropriate.

Female patients should be advised to notify their doctor or pharmacist if they become pregnant during 
therapy with Ofev.

If the patient becomes pregnant while receiving Ofev, treatment must be discontinued and she should 
be apprised of the potential hazard to the foetus.

Breast-feeding
There is no information on the excretion of nintedanib and its metabolites in human milk.
Pre-clinical studies showed that small amounts of nintedanib and its metabolites (≤ 0.5% of the 
administered dose) were secreted into milk of lactating rats. A risk to the newborns/infants cannot be 
excluded. Breast-feeding should be discontinued during treatment with Ofev.

Fertility
Based on preclinical investigations there is no evidence for impairment of male fertility (see 
section 5.3). From subchronic and chronic toxicity studies, there is no evidence that female fertility in 
rats is impaired at a systemic exposure level comparable with that at the maximum recommended 
human dose (MRHD) of 150 mg twice daily (see section 5.3).

4.7 Effects on ability to drive and use machines

Ofev 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 Ofev.

4.8 Undesirable effects

Summary of the safety profile
In clinical trials and during the post-marketing experience, the most frequently reported adverse
reactions associated with the use of nintedanib included diarrhoea, nausea and vomiting, abdominal 
pain, decreased appetite, weight decreased and hepatic enzyme increased.

For the management of selected adverse reactions see section 4.4.



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Tabulated list of adverse reactions
Table 1 provides a summary of the adverse drug reactions (ADRs) by MedDRA System Organ Class
(SOC) and frequency category using the following convention: 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).

Table 1: Summary of ADRs per frequency category
Frequency

System Organ Class
preferred term

Idiopathic pulmonary
fibrosis

Other chronic 
fibrosing ILDs with a 
progressive phenotype

Systemic sclerosis 
associated interstitial 

lung disease
Blood and lymphatic system disorders

Thrombocytopenia Uncommon Uncommon Uncommon
Metabolism and nutrition disorders

Weight decreased Common Common Common
Decreased appetite Common Very common Common
Dehydration Uncommon Uncommon Not known

Cardiac disorders
Myocardial 
infarction

Uncommon Uncommon Not known

Vascular disorders
Bleeding (see 
section 4.4)

Common Common Common

Hypertension Uncommon Common Common
Aneurysms and 
artery dissections

Not known Not known Not known

Gastrointestinal disorder
Diarrhoea Very common Very common Very common
Nausea Very common Very common Very common
Abdominal pain Very common Very common Very common
Vomiting Common Very common Very common
Pancreatitis Uncommon Uncommon Not known
Colitis Uncommon Uncommon Uncommon

Hepatobiliary disorders
Drug induced liver 
injury

Uncommon Common Uncommon

Hepatic enzyme 
increased

Very common Very common Very common

Alanine 
aminotransferase
(ALT) increased

Common Very common Common

Aspartate 
aminotransferase
(AST) increased

Common Common Common

Gamma glutamyl
transferase (GGT) 
increased

Common Common Common

Hyperbilirubinaemia Uncommon Uncommon Not known
Blood alkaline 
phosphatase (ALKP) 
increased

Uncommon Common Common

Skin and subcutaneous tissue disorders
Rash Common Common Uncommon
Pruritus Uncommon Uncommon Uncommon



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Frequency

System Organ Class
preferred term

Idiopathic pulmonary
fibrosis

Other chronic 
fibrosing ILDs with a 
progressive phenotype

Systemic sclerosis 
associated interstitial 

lung disease
Alopecia Uncommon Uncommon Not known

Renal and urinary disorders
Renal failure (see 
section 4.4)

Not known Uncommon Uncommon

Nervous system disorders
Headache Common Common Common

Description of selected adverse reactions

Diarrhoea
In clinical trials (see section 5.1), diarrhoea was the most frequent gastro-intestinal event reported. In 
most patients, the event was of mild to moderate intensity. More than two thirds of patients 
experiencing diarrhoea reported its first onset already during the first three months of treatment. In 
most patients, the events were managed by anti-diarrhoeal therapy, dose reduction or treatment 
interruption (see section 4.4). An overview of the reported diarrhoea events in the clinical trials is 
listed in Table 2:

Table 2: Diarrhoea in clinical trials over 52 weeks

INPULSIS INBUILD SENSCIS

Placebo Ofev Placebo Ofev Placebo Ofev

Diarrhoea 18.4% 62.4% 23.9% 66.9% 31.6% 75.7%

Severe diarrhoea 0.5% 3.3% 0.9% 2.4% 1.0% 4.2%

Diarrhoea 
leading to Ofev 
dose reduction

0% 10.7% 0.9% 16.0% 1.0% 22.2%

Diarrhoea 
leading to Ofev 
discontinuation

0.2% 4.4% 0.3% 5.7% 0.3% 6.9%

Hepatic enzyme increased
In the INPULSIS trials, liver enzyme elevations (see section 4.4) were reported in 13.6% versus 2.6%
of patients treated with Ofev and placebo, respectively. In the INBUILD trial, liver enzyme elevations 
were reported in 22.6% versus 5.7% of patients treated with Ofev and placebo, respectively. In the 
SENSCIS trial, liver enzyme elevations were reported in 13.2% versus 3.1% of patients treated with 
Ofev and placebo, respectively. Elevations of liver enzymes were reversible and not associated with 
clinically manifest liver disease.
For further information about special populations, recommended measures and dosing adjustments in 
case of diarrhoea and hepatic enzyme increased, refer additionally to sections 4.4 and 4.2, 
respectively.

Bleeding
In clinical trials, the frequency of patients who experienced bleeding was slightly higher in patients 
treated with Ofev or comparable between the treatment arms (Ofev 10.3% versus placebo 7.8% for 
INPULSIS; Ofev 11.1% versus placebo 12.7% for INBUILD; Ofev 11.1% versus placebo 8.3% for 
SENSCIS). Non-serious epistaxis was the most frequent bleeding event reported. Serious bleeding 
events occurred with low frequencies in the 2 treatment groups (Ofev 1.3% versus placebo 1.4% for 
INPULSIS; Ofev 0.9% versus placebo 1.5% for INBUILD; Ofev 1.4% versus placebo 0.7% for 
SENSCIS).
Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central 
nervous organ systems, with the most frequent being gastrointestinal (see section 4.4).



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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 Ofev overdose. Two patients in the oncology programme
had an overdose of maximum 600 mg twice daily up to eight days. Observed adverse reactions were 
consistent with the known safety profile of nintedanib, i.e. increased liver enzymes and gastrointestinal 
symptoms. Both patients recovered from these adverse reactions. In the INPULSIS trials, one patient 
was inadvertently exposed to a dose of 600 mg daily for a total of 21 days. A non-serious adverse 
event (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of 
other reported events. 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 small molecule tyrosine kinase inhibitor including the receptors platelet-derived
growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, and 
VEGFR 1-3. In addition, nintedanib inhibits Lck (lymphocyte-specific tyrosine-protein kinase), Lyn
(tyrosine-protein kinase lyn), Src (proto-oncogene tyrosine-protein kinase src), and CSF1R (colony
stimulating factor 1 receptor) kinases. Nintedanib binds competitively to the adenosine triphosphate 
(ATP) binding pocket of these kinases and blocks the intracellular signalling cascades, which have 
been demonstrated to be involved in the pathogenesis of fibrotic tissue remodelling in interstitial lung 
diseases.

Pharmacodynamic effects
In in vitro studies using human cells nintedanib has been shown to inhibit processes assumed to be 
involved in the initiation of the fibrotic pathogenesis, the release of pro-fibrotic mediators from 
peripheral blood monocytic cells and macrophage polarisation to alternatively activated macrophages. 
Nintedanib has been demonstrated to inhibit fundamental processes in organ fibrosis, proliferation and
migration of fibroblasts and transformation to the active myofibroblast phenotype and secretion of 
extracellular matrix. In animal studies in multiple models of IPF, SSc/SSc-ILD, rheumatoid arthritis-
associated-(RA-)ILD and other organ fibrosis, nintedanib has shown anti-inflammatory effects and 
anti-fibrotic effects in the lung, skin, heart, kidney, and liver. Nintedanib also exerted vascular activity. 
It reduced dermal microvascular endothelial cell apoptosis and attenuated pulmonary vascular 
remodelling by reducing the proliferation of vascular smooth muscle cells, the thickness of pulmonary 
vessel walls and percentage of occluded pulmonary vessels.

Clinical efficacy and safety

Idiopathic pulmonary fibrosis (IPF)

The clinical efficacy of nintedanib has been studied in patients with IPF in two phase III, randomised, 
double-blind, placebo-controlled studies with identical design (INPULSIS-1 (1199.32) and 
INPULSIS-2 (1199.34)). Patients with FVC baseline < 50% predicted or carbon monoxide diffusing 
capacity (DLCO, corrected for haemoglobin) < 30% predicted at baseline were excluded from the 
trials. Patients were randomized in a 3:2 ratio to treatment with Ofev 150 mg or placebo twice daily 
for 52 weeks.

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


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

Annual rate of decline in FVC
The annual rate of decline of FVC (in mL) was significantly reduced in patients receiving nintedanib 
compared to patients receiving placebo. The treatment effect was consistent in both trials. See Table 3
for individual and pooled study results.

Table 3: Annual rate of decline in FVC (mL) in trials INPULSIS-1, INPULSIS-2 and their 
pooled data - treated set

INPULSIS-1 INPULSIS-2

INPULSIS-1 and 
INPULSIS-2

pooled
Placebo Ofev

150 mg 
twice daily

Placebo Ofev
150 mg 

twice daily

Placebo Ofev
150 mg 

twice daily
Number of 
analysed 
patients 204 309 219 329 423 638
Rate1 (SE) of 
decline over 52 
weeks

−239.9 
(18.71)

−114.7 
(15.33)

−207.3 
(19.31)

−113.6 
(15.73)

−223.5 
(13.45)

−113.6 
(10.98)

Comparison vs placebo
Difference1 125.3 93.7 109.9

95% CI (77.7, 
172.8)

(44.8, 
142.7)

(75.9, 
144.0)

p-value <0.0001 0.0002 <0.0001
1 Estimated based on a random coefficient regression model. 
CI: confidence interval

In a sensitivity analysis which assumed that in patients with missing data at week 52 the FVC decline 
after the last observed value would be the same as in all placebo patients, the adjusted difference in the 
annual rate of decline between nintedanib and placebo was 113.9 mL/year (95% CI 69.2, 158.5) in 
INPULSIS-1 and 83.3 mL/year (95% CI 37.6, 129.0) in INPULSIS-2.

See Figure 1 for the evolution of change from baseline over time in both treatment groups, based on 
the pooled analysis of studies INPULSIS-1 and INPULSIS-2.



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

bid = twice daily

FVC responder analysis
In both INPULSIS trials, the proportion of FVC responders, defined as patients with an absolute 
decline in FVC % predicted no greater than 5% (a threshold indicative of the increasing risk of 
mortality in IPF), was significantly higher in the nintedanib group as compared to placebo. Similar 
results were observed in analyses using a conservative threshold of 10%. See Table 4 for individual 
and pooled study results.



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Table 4: Proportion of FVC responders at 52 weeks in trials INPULSIS-1, INPULSIS-2 
and their pooled data - treated set

INPULSIS-1 INPULSIS-2

INPULSIS-1 and 
INPULSIS-2 

pooled
Placebo Ofev

150 mg 
twice daily

Placebo Ofev
150 mg 

twice daily

Placebo Ofev
150 mg 

twice daily
Number of 
analysed 
patients 204 309 219 329 423 638
5% threshold
Number (%) of 
FVC 
responders1 78 (38.2) 163 (52.8) 86 (39.3) 175 (53.2) 164 (38.8) 338 (53.0)
Comparison vs placebo 

Odds ratio 1.85 1.79 1.84
95% CI (1.28, 2.66) (1.26, 2.55) (1.43, 2.36)
p-value2 0.0010 0.0011 <0.0001

10% threshold
Number (%) of 
FVC 
responders1 116 (56.9) 218 (70.6) 140 (63.9) 229 (69.6) 256 (60.5) 447 (70.1)
Comparison vs placebo 

Odds ratio 1.91 1.29 1.58
95% CI (1.32, 2.79) (0.89, 1.86) (1.21, 2.05)
p-value2 0.0007 0.1833 0.0007

1Responder patients are those with no absolute decline greater than 5% or greater than 10% in FVC % predicted, 
depending on the threshold and with an FVC evaluation at 52 weeks.
2Based on a logistic regression. 

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

Table 5: Frequency of patients with ≥ 10% absolute decline of FVC % predicted or death
over 52 weeks and time to progression in trials INPULSIS-1, INPULSIS-2, and 
their pooled data - treated set

INPULSIS-1 INPULSIS-2

INPULSIS-1 and 
INPULSIS-2 

pooled
Placebo Ofev

150 mg 
twice daily

Placebo Ofev
150 mg 

twice daily

Placebo Ofev
150 mg 

twice daily
Number at risk 204 309 219 329 423 638
Patients with 
events, N (%)

83 
(40.7)

75
(24.3)

92
(42.0)

98 
(29.8)

175
(41.4)

173
(27.1)

Comparison vs placebo1

p-value2 0.0001 0.0054 <0.0001
Hazard ratio3 0.53 0.67 0.60
95% CI (0.39, 0.72) (0.51, 0.89) (0.49, 0.74)

1 Based on data collected up to 372 days (52 weeks + 7 day margin).
2 Based on a Log-rank test.
3 Based on a Cox’s regression model.



14

Change from baseline in SGRQ total score at week 52
In the pooled analysis of the INPULSIS trials, the baseline SGRQ scores were 39.51 in the nintedanib 
group and 39.58 in the placebo group. The estimated mean change from baseline to week 52 in SGRQ 
total score was smaller in the nintedanib group (3.53) than in the placebo group (4.96), with a 
difference between the treatment groups of -1.43 (95% CI: -3.09, 0.23; p=0.0923). Overall, the effect 
of nintedanib on health-related quality of life as measured by the SGRQ total score is modest, 
indicating less worsening compared to placebo.

Time to first acute IPF exacerbation
In the pooled analysis of the INPULSIS trials, a numerically lower risk of first acute exacerbation was 
observed in patients receiving nintedanib compared to placebo. See Table 6 for individual and pooled 
study results.

Table 6: Frequency of patients with acute IPF exacerbations over 52 weeks and time to 
first exacerbation analysis based on investigator-reported events in trials 
INPULSIS-1, INPULSIS-2, and their pooled data - treated set

INPULSIS-1 INPULSIS-2

INPULSIS-1 and 
INPULSIS-2 

pooled
Placebo Ofev

150 mg 
twice daily

Placebo Ofev
150 mg 

twice daily

Placebo Ofev
150 mg 

twice daily
Number at risk 204 309 219 329 423 638
Patients with events, 
N (%) 11 (5.4) 19 (6.1) 21 (9.6) 12 (3.6) 32 (7.6) 31 (4.9)
Comparison vs placebo1

p-value2 0.6728 0.0050 0.0823
Hazard ratio3 1.15 0.38 0.64
95% CI (0.54, 2.42) (0.19, 0.77) (0.39, 1.05)

1 Based on data collected up to 372 days (52 weeks + 7 day margin).
2 Based on a Log-rank test.
3 Based on a Cox’s regression model.

In a pre-specified sensitivity analysis, the frequency of patients with at least 1 adjudicated 
exacerbation occurring within 52 weeks was lower in the nintedanib group (1.9% of patients) than in 
the placebo group (5.7% of patients). Time to event analysis of the adjudicated exacerbation events 
using pooled data yielded a hazard ratio (HR) of 0.32 (95% CI 0.16, 0.65; p=0.0010).

Survival analysis
In the pre-specified pooled analysis of survival data of the INPULSIS trials, overall mortality over 
52 weeks was lower in the nintedanib group (5.5%) compared with the placebo group (7.8%). The 
analysis of time to death resulted in a HR of 0.70 (95% CI 0.43, 1.12; p=0.1399). The results of all 
survival endpoints (such as on-treatment mortality and respiratory mortality) showed a consistent 
numerical difference in favour of nintedanib.



15

Table 7: All-cause mortality over 52 weeks in trials INPULSIS-1, INPULSIS-2, and their 
pooled data - treated set

INPULSIS-1 INPULSIS-2

INPULSIS-1 and 
INPULSIS-2 

pooled

Placebo Ofev

150 mg 
twice daily

Placebo Ofev

150 mg 
twice daily

Placebo Ofev

150 mg 
twice daily

Number at risk 204 309 219 329 423 638

Patients with events, 
N (%) 13 (6.4) 13 (4.2) 20 (9.1) 22 (6.7) 33 (7.8) 35 (5.5)

Comparison vs placebo1

p-value2
0.2880 0.2995 0.1399

Hazard ratio3
0.63 0.74 0.70

95% CI (0.29, 1.36) (0.40, 1.35) (0.43, 1.12)
1 Based on data collected up to 372 days (52 weeks + 7 day margin).
2 Based on a Log-rank test.
3 Based on a Cox’s regression model.

Long-term treatment with Ofev in patients with IPF (INPULSIS-ON)
An open-label extension trial of Ofev included 734 patients with IPF. Patients who completed the 52-
week treatment period in an INPULSIS trial received open-label Ofev treatment in the extension trial 
INPULSIS-ON. Median exposure time for patients treated with Ofev in both the INPULSIS and 
INPULSIS-ON trials was 44.7 months (range 11.9 – 68.3). The exploratory efficacy endpoints 
included the annual rate of decline in FVC over 192 weeks which was −135.1 (5.8) mL/year in all 
patients treated and were consistent with the annual rate of FVC decline in patients treated with Ofev
in the INPULSIS phase III trials (−113.6 mL per year). The adverse event profile of Ofev in 
INPULSIS-ON was consistent to that in the INPULSIS phase III trials.

IPF patients with advanced lung function impairment (INSTAGE)
INSTAGE was a multicentre, multinational, prospective, randomised, double-blind, parallel-group 
clinical trial in IPF patients with advanced lung function impairment (DLCO ≤ 35% predicted) for 24 
weeks. 136 patients were treated with Ofev monotherapy. Primary endpoint result showed a reduction 
of St Georges Respiratory Questionnaire (SGRQ) total score by -0.77 units at week W12, based on 
adjusted mean change from baseline. A post hoc comparison demonstrated that the decline in FVC in 
these patients was consistent with the decline in FVC in patients with less advanced disease and 
treated with Ofev in the INPULSIS phase III trials.
The safety and tolerability profile of Ofev in IPF patients with advanced lung function impairment was 
consistent with that seen in the INPULSIS phase III trials.

Additional data from the phase IV INJOURNEY trial with Ofev 150 mg twice daily and add-on 
pirfenidone
Concomitant treatment with nintedanib and pirfenidone has been investigated in an exploratory open-
label, randomised trial of nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg 
three times a day) compared to nintedanib 150 mg twice daily alone in 105 randomised patients for 12 
weeks. The primary endpoint was the percentage of patients with gastrointestinal adverse events from 
baseline to week 12. Gastrointestinal adverse events were frequent and in line with the established 
safety profile of each component. Diarrhoea, nausea and vomiting were the most frequent adverse 
events reported in patients, treated with pirfenidone added to nintedanib versus nintedanib alone, 
respectively.
Mean (SE) absolute changes from baseline in FVC at week 12 were −13.3 (17.4) mL in patients 
treated with nintedanib with add-on pirfenidone (n=48) compared to −40.9 (31.4) mL in patients 
treated with nintedanib alone (n=44).



16

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

The clinical efficacy of Ofev has been studied in patients with other chronic fibrosing ILDs with a 
progressive phenotype in a double-blind, randomised, placebo-controlled phase III trial (INBUILD). 
Patients with IPF were excluded. Patients with a clinical diagnosis of a chronic fibrosing ILD were 
selected if they had relevant fibrosis (greater than 10% fibrotic features) on HRCT and presented 
with clinical signs of progression (defined as FVC decline ≥10%, FVC decline ≥ 5% and <10% 
with worsening symptoms or imaging, or worsening symptoms and worsening imaging all in the 
24 months prior to screening). Patients were required to have an FVC greater than or equal to 45% 
of predicted and a DLCO 30% to less than 80% of predicted. Patients were required to have 
progressed despite management deemed appropriate in clinical practice for the patient’s relevant 
ILD.

A total of 663 patients were randomised in a 1:1 ratio to receive either Ofev 150 mg bid or matching 
placebo for at least 52 weeks. The median Ofev exposure over the whole trial was 17.4 months and the 
mean Ofev exposure over the whole trial was 15.6 months. Randomisation was stratified based on 
HRCT fibrotic pattern as assessed by central readers. 412 patients with HRCT with usual interstitial 
pneumonia (UIP)-like fibrotic pattern and 251 patients with other HRCT fibrotic patterns were 
randomised. There were 2 co-primary populations defined for the analyses in this trial: all patients (the 
overall population) and patients with HRCT with UIP-like fibrotic pattern. Patients with other HRCT 
fibrotic patterns represented the ‘complementary’ population.

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

Patients had a mean (standard deviation [SD, Min-Max]) age of 65.8 (9.8, 27-87) years and a mean 
FVC percent predicted of 69.0% (15.6, 42-137). The underlying clinical ILD diagnoses in groups 
represented in the trial were hypersensitivity pneumonitis (26.1%), autoimmune ILDs (25.6%), 
idiopathic nonspecific interstitial pneumonia (18.9%), unclassifiable idiopathic interstitial pneumonia 
(17.2%), and other ILDs (12.2%).

The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in 
specific diagnostic subgroups. Consistent effects were demonstrated in subgroups based on the ILD 
diagnoses. The experience with nintedanib in very rare progressive fibrosing ILDs is limited.

Annual rate of decline in FVC
The annual rate of decline in FVC (in mL) over 52 weeks was significantly reduced by 107.0 mL in 
patients receiving Ofev compared to patients receiving placebo (Table 8) corresponding to a relative 
treatment effect of 57.0%.

Table 8: Annual rate of decline in FVC (mL) over 52 weeks

Placebo Ofev
150 mg twice daily

Number of analysed patients 331 332
Rate1 (SE) of decline over 
52 weeks -187.8 (14.8) -80.8 (15.1)
Comparison vs placebo
Difference1 107.0

95% CI (65.4, 148.5)
p-value < 0.0001

1Based on a random coefficient regression with fixed categorical effects of treatment, HRCT pattern, fixed 
continuous effects of time, baseline FVC [mL], and including treatment-by-time and baseline-by-time 
interactions



17

Similar results were observed in the co-primary population of patients with HRCT with UIP-like 
fibrotic pattern. The treatment effect was consistent in the complementary population of patients with 
other HRCT fibrotic patterns (interaction p-value 0.2268) (Figure 2).

Figure 2 Forest plot of the annual rate of decline in FVC (mL) over 52 weeks in the 
patient populations

bid = twice daily

The results of the effect of Ofev in reducing the annual rate of decline in FVC were confirmed by all 
pre-specified sensitivity analyses and consistent results were observed in the pre-specified efficacy 
subgroups: gender, age group, race, predicted baseline FVC %, and original underlying clinical ILD 
diagnosis in groups.

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



18

Figure 3 Mean (SEM) observed FVC change from baseline (mL) over 52 weeks

bid = twice daily

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

FVC responder analysis
The proportion of FVC responders, defined as patients with a relative decline in FVC % predicted no 
greater than 5%, was higher in the Ofev group as compared to placebo. Similar results were observed 
in analyses using a threshold of 10% (Table 9).



19

Table 9: Proportion of FVC responders at 52 weeks in INBUILD

Placebo Ofev

150 mg twice daily

Number of analysed patients 331 332

5% threshold

Number (%) of FVC 
responders1 104 (31.4) 158 (47.6)

Comparison vs placebo 

Odds ratio² 2.01

95% CI (1.46, 2.76)

Nominal p-value < 0.0001

10% threshold

Number (%) of FVC 
responders1 169 (51.1) 197 (59.3)

Comparison vs placebo 

Odds ratio² 1.42

95% CI (1.04, 1.94)

Nominal p-value 0.0268
1Responder patients are those with no relative decline greater than 5% or greater than 10% in FVC % predicted, 
depending on the threshold and with an FVC evaluation at 52 weeks (patients with missing data at week 52 were 
considered as non-responders).
2Based on a logistic regression model with continuous covariate baseline FVC % predicted and binary covariate 
HRCT pattern

Time to first acute ILD exacerbation or death
Over the whole trial, the proportion of patients with at least one event of first acute ILD exacerbation 
or death was 13.9% in the Ofev group and 19.6% in the placebo group. The HR was 0.67 (95% CI: 
0.46, 0.98; nominal p=0.0387), indicating a 33% reduction in the risk of first acute ILD exacerbation 
or death in patients receiving Ofev compared to placebo (Figure 4).



20

Figure 4 Kaplan–Meier plot of time to first acute ILD exacerbation or death over the 
whole trial

bid = twice daily

Survival analysis
The risk of death was lower in the Ofev group compared to the placebo group. The HR was 0.78 (95% 
CI: 0.50, 1.21; nominal p=0.2594), indicating a 22% reduction in the risk of death in patients receiving 
Ofev compared to placebo.

Time to progression (≥ 10% absolute decline of FVC % predicted) or death
In the INBUILD trial, the risk of progression (≥ 10% absolute decline of FVC % predicted) or death 
was reduced for patients treated with Ofev. The proportion of patients with an event was 35.2% in the 
Ofev group and 48.3% in the placebo group. The HR was 0.66 (95% CI: 0.53, 0.83; p=0.0003), 
indicating a 34% reduction of the risk of progression (≥ 10% absolute decline of FVC % predicted) or 
death in patients receiving Ofev compared to placebo.

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

The adjusted mean absolute change from baseline in Living with Pulmonary Fibrosis (L-PF)
symptoms dyspnoea domain score at week 52 was 4.28 in the Ofev group compared with 7.81 in the 
placebo group. The adjusted mean difference between the groups in favour of Ofev was -3.53 (95% 
CI: -6.14, -0.92; nominal p=0.0081). The adjusted mean absolute change from baseline in L-PF 
Symptoms cough domain score at week 52 was -1.84 in the Ofev group compared with 4.25 in the 
placebo group. The adjusted mean difference between the groups in favour of Ofev was -6.09 (95% 
CI: -9.65, -2.53; nominal p=0.0008).



21

Systemic sclerosis associated interstitial lung disease (SSc-ILD)

The clinical efficacy of Ofev has been studied in in patients with SSc-ILD in a double-blind, 
randomised, placebo-controlled phase III trial (SENSCIS). Patients were diagnosed with SSc-ILD 
based upon the 2013 American College of Rheumatology / European League Against Rheumatism 
classification criteria for SSc and a chest high resolution computed tomography (HRCT) scan 
conducted within the previous 12 months. A total of 580 patients were randomised in a 1:1 ratio to 
receive either Ofev 150 mg bid or matching placebo for at least 52 weeks, of which 576 patients were 
treated. Randomisation was stratified by antitopoisomerase antibody status (ATA). Individual patients 
stayed on blinded trial treatment for up to 100 weeks (median Ofev exposure 15.4 months; mean Ofev 
exposure 14.5 months).

The primary endpoint was the annual rate of decline in FVC over 52 weeks. Key secondary endpoints 
were absolute change from baseline in the modified Rodnan Skin Score (mRSS) at week 52 and 
absolute change from baseline in the Saint George’s Respiratory Questionnaire (SGRQ) total score at 
week 52.

In the overall population, 75.2% of the patients were female. The mean (standard deviation [SD, Min-
Max]) age was 54.0 (12.2, 20-79) years. Overall, 51.9% of patients had diffuse cutaneous systemic 
sclerosis (SSc) and 48.1% had limited cutaneous SSc. The mean (SD) time since first onset of a non-
Raynaud symptom was 3.49 (1.7) years. 49.0% of patients were on stable therapy with mycophenolate 
at baseline. The safety profile in patients with or without mycophenolate at baseline was comparable.

Annual rate of decline in FVC
The annual rate of decline of FVC (mL) over 52 weeks was significantly reduced by 41.0 mL in 
patients receiving Ofev compared to patients receiving placebo (Table 10) corresponding to a relative 
treatment effect of 43.8%.

Table 10: Annual rate of decline in FVC (mL) over 52 weeks

Placebo Ofev

150 mg twice daily

Number of analysed patients 288 287

Rate1 (SE) of decline over 
52 weeks

-93.3 (13.5) -52.4 (13.8)

Comparison vs placebo

Difference1 41.0

95% CI (2.9, 79.0)

p-value <0.05
1Based on a random coefficient regression with fixed categorical effects of treatment, ATA status, gender, fixed 

continuous effects of time, baseline FVC [mL], age, height, and including treatment-by-time and baseline-by-

time interactions. Random effect was included for patient specific intercept and time. Within-patient errors were 

modelled by an unstructured variance-covariance matrix. Inter-individual variability was modelled by a 

variance-components variance-covariance matrix.

The effect of Ofev in reducing the annual rate of decline in FVC was similar across pre-specified 
sensitivity analyses and no heterogeneity was detected in pre-specified subgroups (e.g. by age, gender, 
and mycophenolate use).

In addition, similar effects were observed on other lung function endpoints, e.g absolute change from 
baseline in FVC in mL at week 52 (Figure 5 and Table 11) and rate of decline in FVC in % predicted 
over 52 weeks (Table 12) providing further substantiation of the effects of Ofev on slowing 
progression of SSc-ILD. Furthermore, fewer patients in the Ofev group had an absolute FVC decline 
> 5% predicted (20.6% in the Ofev group vs. 28.5% in the placebo group, OR=0.65, p=0.0287). The 
relative FVC decline in mL > 10% was comparable between both groups (16.7% in the Ofev group vs. 



22

18.1% in the placebo group, OR=0.91, p=0.6842). In these analyses, missing FVC values at week 52 
were imputed with the patient’s worst value on treatment.

An exploratory analysis of data up to 100 weeks (maximum treatment duration in SENSCIS) 
suggested that the on treatment effect of Ofev on slowing progression of SSc-ILD persisted beyond 
52 weeks.

Figure 5: Mean (SEM) observed FVC change from baseline (mL) over 52 weeks

bid = twice daily

Table 11: Absolute change from baseline in FVC (mL) at week 52

Placebo Ofev

150 mg twice daily

Number of analysed patients 288 288

Mean (SD) at Baseline 2541.0 (815.5) 2458.5 (735.9)

Mean1 (SE) change from 
baseline at week 52

-101.0 (13.6) -54.6 (13.9)

Comparison vs placebo

Mean1 46.4

95% CI (8.1, 84.7)

p-value <0.05
1Based on Mixed Model for Repeated Measures (MMRM), with fixed categorical effects of ATA status, visit, 
treatment-by-visit interaction, baseline-by-visit interaction age, gender and height. Visit was the repeated 
measure. Within-patient errors were modelled by unstructured variance-covariance structure. Adjusted mean was 
based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).



23

Table 12: Annual rate of decline in FVC (% predicted) over 52 weeks

Placebo Ofev

150 mg twice daily

Number of analysed patients 288 287

Rate1 (SE) of decline over 
52 weeks

-2.6 (0.4) -1.4 (0.4)

Comparison vs placebo

Difference1 1.15

95% CI (0.09, 2.21)

p-value <0.05
1Based on a random coefficient regression with fixed categorical effects of treatment, ATA status, fixed 
continuous effects of time, baseline FVC [% pred], and including treatment-by-time and baseline-by-time 
interactions. Random effect was included for patient specific intercept and time. Within-patient errors were 
modelled by an unstructured variance-covariance matrix. Inter-individual variability was modelled by a 
variance-components variance-covariance matrix

Change from baseline in Modified Rodnan Skin Score (mRSS) at week 52
The adjusted mean absolute change from baseline in mRSS at week 52 was comparable between the 
Ofev group (-2.17 (95% CI -2.69, -1.65)) and the placebo group (-1.96 (95% CI -2.48, -1.45)). The 
adjusted mean difference between the treatment groups was -0.21 (95% CI -0.94, 0.53; p = 0.5785).

Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score at week 52
The adjusted mean absolute change from baseline in SGRQ total score at week 52 was comparable 
between the Ofev group (0.81 (95% CI -0.92, 2.55)) and the placebo group (-0.88 (95% CI -2.58, 
0.82)). The adjusted mean difference between the treatment groups was 1.69 (95% CI -0.73, 4.12; 
p = 0.1711).

Survival analysis
Mortality over the whole trial was comparable between the Ofev group (N = 10; 3.5%) and the 
placebo group (N = 9; 3.1%). The analysis of time to death over the whole trial resulted in a HR of 
1.16 (95% CI 0.47, 2.84; p = 0.7535).

QT interval
In a dedicated study in renal cell cancer patients, QT/QTc measurements were recorded and showed 
that a single oral dose of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib 
administered twice daily for 15 days did not prolong the QTcF interval.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Ofev 
in all subsets of the paediatric population in IPF (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption
Nintedanib reached maximum plasma concentrations approximately 2 - 4 h after oral administration as 
soft gelatine capsule under fed conditions (range 0.5 - 8 h). 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 h; 
fed: 3.98 h).



24

Distribution
Nintedanib follows at least bi-phasic disposition kinetics. After intravenous infusion, a high volume of 
distribution (Vss: 1,050 L, 45.0% gCV) was observed.

The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. 
Serum albumin is considered to be the major binding protein. Nintedanib is preferentially 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 uridine 5'-diphospho-
glucuronosyltransferase enzymes (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. Nintedanib, BIBF 1202, and BIBF 1202 glucuronide 
did not inhibit or induce CYP enzymes in preclinical studies, either. Drug-drug interactions between 
nintedanib and CYP substrates, CYP inhibitors, or CYP inducers are therefore not expected.

Elimination
Total plasma clearance after intravenous infusion was high (CL: 1,390 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 the dose (24.2% gCV) after intravenous administration; the renal 
clearance was 20 mL/min (32.6% gCV). The major route of elimination of drug related radioactivity 
after oral administration of [14C] nintedanib was via faecal/biliary excretion (93.4% of dose, 
2.61% gCV). The contribution of renal excretion to the total clearance was low (0.649% of dose, 
26.3% gCV). The overall recovery was considered complete (above 90%) within 4 days after dosing. 
The terminal half-life of nintedanib was between 10 and 15 h (gCV % approximately 50%).

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

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.

Population pharmocokinetic analysis in special populations
The PK properties of nintedanib were similar in healthy volunteers, patients with IPF, patients with 
other chronic fibrosing ILDs with a progressive phenotype, patients with SSc-ILD, and cancer 
patients. Based on results of a population PK (PopPK) analysis in patients with IPF and non small cell 
lung cancer (NSCLC) (N=1,191) and descriptive investigations, exposure to nintedanib was not 
influenced by sex (body weight corrected), mild and moderate renal impairment (estimated by 
creatinine clearance), alcohol consumption, or P-gp genotype. 
PopPK 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 moderate 
effects are considered not clinically relevant (see section 4.4).



25

Age
Exposure to nintedanib increased linearly with age. AUCτ,ss decreased by 16% for a 45-year old patient 
and increased by 13% for a 76-year old patient 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. Based on a PopPK model, an increase in nintedanib exposure of approximately 
20 - 25% was observed in patients ≥ 75 years compared with patients under 65 years.

Studies in paediatric populations have not been performed.

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

increased by 25% for a 50 kg patient (5th percentile) and decreased by 19% for a 100 kg patient 
(95th percentile) relative to a patient with the median weight of 71.5 kg.

Race
The population mean exposure to nintedanib was 33 - 50% higher in Chinese, Taiwanese, and Indian 
patients and 16% higher in Japanese patients while it was 16 - 22% lower in Koreans compared to 
Caucasians (body weight corrected). Data from Black individuals were very limited but in the same 
range as for Caucasians.

Hepatic impairment
In a dedicated single dose phase I study and compared to healthy subjects, exposure to nintedanib 
based on Cmax and AUC was 2.2-fold higher in volunteers with mild hepatic impairment (Child 
Pugh A; 90% CI 1.3 – 3.7 for Cmax and 1.2 – 3.8 for AUC, respectively). In volunteers with moderate 
hepatic impairment (Child Pugh B), exposure was 7.6-fold higher based on Cmax (90% CI 4.4 – 13.2) 
and 8.7-fold higher (90% CI 5.7 – 13.1) based on AUC, respectively, compared to healthy volunteers. 
Subjects with severe hepatic impairment (Child Pugh C) have not been studied.

Concomitant treatment with pirfenidone
In a dedicated pharmacokinetic study, concomitant treatment of nintedanib with pirfenidone was 
investigated in patients with IPF. Group 1 received a single dose of 150 mg nintedanib before and after 
uptitration to 801 mg pirfenidone three times a day at steady state (N=20 patients treated). Group 2 
received steady state treatment of 801 mg pirfenidone three times a day and had a PK profiling before 
and after at least 7 days of co-treatment with 150 mg nintedanib twice daily (N=17 patients treated). In 
group 1, the adjusted geometric mean ratios (90% confidence interval (CI)) were 93% (57% - 151%) 
and 96% (70% - 131%) for Cmax and AUC0-tz of nintedanib, respectively (n=12 for intraindividual 
comparison). In group 2, the adjusted geometric mean ratios (90% CI)) were 97% (86% - 110%) and 
95% (86% - 106%) for Cmax,ss and AUCτ,ss of pirfenidone, respectively (n=12 for intraindividual 
comparison).
Based on these results, there is no evidence of a relevant pharmacokinetic drug-drug interaction 
between nintedanib and pirfenidone when administered in combination (see section 4.4).

Concomitant treatment with bosentan
In a dedicated pharmacokinetic study, concomitant treatment of Ofev with bosentan was investigated 
in healthy volunteers. Subjects received a single dose of 150 mg Ofev before and after multiple dosing 
of 125 mg bosentan twice daily at steady state. The adjusted geometric mean ratios (90% confidence 
interval (CI)) were 103% (86% - 124%) and 99% (91% - 107%) for Cmax and AUC0-tz of nintedanib, 
respectively (n=13), indicating that co-administration of nintedanib with bosentan did not alter the 
pharmacokinetics of nintedanib.

Concomitant treatment with oral hormonal contraceptives
In a dedicated pharmacokinetic study, female patients with SSc-ILD received a single dose of a 
combination of 30 µg ethinylestradiol and 150 µg levonorgestrel before and after twice daily dosing of 
150 mg nintedanib for at least 10 days. The adjusted geometric mean ratios (90% confidence interval 
(CI)) were 117% (108% - 127%; Cmax) and 101% (93% - 111%; AUC0–tz) for ethinylestradiol and 
101% (90% - 113%; Cmax) and 96% (91% - 102%; AUC0–tz) for levonorgestrel, respectively (n=15), 



26

indicating that co-administration of nintedanib has no relevant effect on the plasma exposure of 
ethinylestradiol and levonorgestrel.

Exposure-response relationship
Exposure-response analyses of patients with IPF and other chronic fibrosing ILDs with a progressive 
phenotype, indicated a weak relationship between nintedanib plasma exposure and ALT and/or AST 
elevations. Actual administered dose might be the better predictor for the risk of developing diarrhoea 
of any intensity, even if plasma exposure as risk determining factor could not be ruled out (see section 
4.4).

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
In rats, embryo-foetal lethality and teratogenic effects were observed at exposure levels below human 
exposure at the MRHD of 150 mg twice daily. Effects on the development of the axial skeleton and on 
the development of the great arteries were also noted at subtherapeutic exposure levels. 

In rabbits, embryo-foetal lethality and teratogenic effects were observed at an exposure approximately 
3 times higher than at the MRHD but equivocal effects on the embryo-foetal development of the axial 
skeleton and the heart were noted already at an exposure below that at the MRHD of 150 mg twice 
daily. 

In a pre- and postnatal development study in rats, effects on pre- and post-natal development were 
seen at an exposure below the MRHD.

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

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

From the 2-year carcinogenicity studies in mice and rats, there was no evidence for a carcinogenic 
potential of nintedanib.

Genotoxicity studies indicated no mutagenic potential for nintedanib.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
triglycerides, medium-chain
hard fat



27

lecithin (soya) (E322)

Capsule shell
gelatin
glycerol (85%)
titanium dioxide (E171)
iron oxide red (E172)
iron oxide yellow (E172)

Printing ink
shellac glaze
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 

Ofev 100 mg soft capsules
Ofev 100 mg soft capsules are available in the following pack-sizes:
- 30 x 1 soft capsules in aluminium/aluminium perforated unit dose blisters
- 60 x 1 soft capsules in aluminium/aluminium perforated unit dose blisters

Ofev 150 mg soft capsules
Ofev 150 mg soft capsules are available in the following pack-sizes:
- 30 x 1 soft capsules in aluminium/aluminium perforated unit dose blisters
- 60 x 1 soft capsules in aluminium/aluminium perforated unit dose blisters

Not all pack sizes may be marketed.

6.6 Special precautions for disposal 

Any unused medicinal 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



28

8. MARKETING AUTHORISATION NUMBER(S) 

Ofev 100 mg soft capsules
EU/1/14/979/001
EU/1/14/979/002

Ofev 150 mg soft capsules
EU/1/14/979/003
EU/1/14/979/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 January 2015
Date of latest renewal: 23 September 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


29

ANNEX II

A. MANUFACTURER 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



30

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

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

Boehringer Ingelheim France
100-104 Avenue de France
75013 Paris
FRANCE

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

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 (PSURs)

The requirements for submission of PSURs 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 marketing authorisation holder (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.



31

ANNEX III

LABELLING AND PACKAGE LEAFLET



32

A. LABELLING



33

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer box

1. NAME OF THE MEDICINAL PRODUCT

Ofev 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 lecithin. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

30 x 1 soft capsules
60 x 1 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.



34

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
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/14/979/001
EU/1/14/979/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Ofev 100 mg 

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

!"#
$%#
%%#



35

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer box

1. NAME OF THE MEDICINAL PRODUCT

Ofev 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 lecithin. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

30 x 1 soft capsules
60 x 1 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.



36

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
55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/14/979/003
EU/1/14/979/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Ofev 150 mg 

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

!"#
$%#
%%#



37

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

Ofev 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.



38

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

Ofev 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.



39

B. PACKAGE LEAFLET



40

Package leaflet: Information for the patient

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

1. What Ofev is and what it is used for

Ofev contains the active substance nintedanib, a medicine belonging to the class of so-called tyrosine 
kinase inhibitors, and it is used for the treatment of idiopathic pulmonary fibrosis (IPF), other chronic 
fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis 
associated interstitial lung disease (SSc-ILD) in adults.

Idiopathic pulmonary fibrosis (IPF)
IPF is a condition in which the tissue in your lungs becomes thickened, stiff and scarred over time. As 
a result, scarring reduces the ability to transfer oxygen from the lungs into the bloodstream and it 
becomes difficult to breathe deeply. Ofev helps to reduce scarring and stiffening of the lungs.

Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype
Besides IPF, there are other conditions in which the tissue in your lungs becomes thickened, stiff, and 
scarred over time (lung fibrosis) and keeps worsening (progressive phenotype). Examples of these 
conditions are hypersensitivity pneumonitis, autoimmune ILDs (e.g. rheumatoid arthritis associated 
ILD), idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, 
and other ILDs. Ofev helps to reduce further scarring and stiffening of the lungs.

Systemic sclerosis associated interstitial lung disease (SSc-ILD)
Systemic sclerosis (SSc), also known as scleroderma, is a rare chronic autoimmune disease that affects 
connective tissue in many parts of the body. SSc causes fibrosis (scarring and stiffening) of the skin 
and other internal organs such as the lungs. When the lungs are affected by fibrosis, it is called 
interstitial lung disease (ILD), and so the condition is called SSc-ILD. Fibrosis in the lungs reduces the 
ability to transfer oxygen into the bloodstream, and breathing capacity is reduced. Ofev helps to reduce 
further scarring and stiffening of the lungs.

2. What you need to know before you take Ofev

Do not take Ofev
- if you are pregnant,



41

- if you are allergic to nintedanib, peanut or soya, or any of the other ingredients of this medicine 
(listed in section 6).

Warnings and precautions 
Talk to your doctor or pharmacist before taking Ofev,
- if you have or ever had liver problems, 
- if you have or ever had problems with your kidney,
- if you have or ever had bleeding problems,
- if you take blood-thinning medicines (such as warfarin, phenprocoumon or heparin) to prevent 

blood clotting,
- if you take pirfenidone as this may increase the risk of having diarrhoea, nausea, vomiting and liver 

problems,
- if you have or ever had problems with your heart (for example a heart attack),
- if you have recently had surgery. Nintedanib may affect the way your wounds heal. Therefore, your 

treatment with Ofev will usually be stopped for a while if you are having a surgery. Your doctor 
will decide when to resume your treatment with this medicine.

- if you have high blood pressure,
- if you have abnormally high blood pressure in the blood vessels of the lungs (pulmonary

hypertension),
- 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 do some blood tests, for example to check your liver 
function. Your doctor will discuss the results of these tests with you and decide whether you may 
receive Ofev.

Inform your doctor immediately while taking this medicine, 
- if you get diarrhoea. Treating diarrhoea early 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 have severe pain in your stomach, 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’). Also, tell your doctor if you had peptic ulcers or diverticular disease in the past, or 
are concomitantly treated with anti-inflammatory drugs (NSAIDs) (used to treat pain relief and 
swelling) or steroids (used for inflammation and allergies), as this may increase this risk;

- if you have a combination of severe pain or cramping in your stomach, red blood in your stool or 
diarrhea as these could be symptoms of a bowel inflammation from inadequate blood supply;

- if you have pain, swelling, reddening, warmth of a limb as this could be symptoms of a blood clot 
in one of your veins (a type of blood vessel);

- if you have 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 you have any major bleeding.

Children and adolescents
Ofev should not be taken by children and adolescents under 18 years of age.

Other medicines and Ofev
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.

Ofev can interact with certain other medicines. The following medicines are examples that may 
increase the levels of nintedanib in your blood, and hence may increase the risk for side effects (see 
section 4):



42

- a medicine used to treat fungal infections (ketoconazole)
- a medicine used to treat bacterial infections (erythromycin)
- a medicine that affects your immune system (cyclosporine)

The following medicines are examples that may lower the levels of nintedanib in your blood and thus 
may reduce the effectiveness of Ofev:
- an antibiotic used to treat tuberculosis (rifampicin)
- medicines to treat seizures (carbamazepine, phenytoin)
- a herbal medicine to treat depression (St. John’s Wort)

Pregnancy and breast-feeding
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.

Pregnancy
Do not take this medicine during pregnancy, as it can harm your unborn baby and cause birth defects.

You must have a pregnancy test done to ensure you are not pregnant before starting treatment with 
Ofev. Please talk to your doctor.

Contraception
- Women who can become pregnant must use a highly effective method of birth control to prevent 

pregnancy when they start taking Ofev, while they are taking Ofev and for at least 3 months after 
stopping treatment.

- You should discuss the most appropriate methods of contraception for you with your doctor.
- Vomiting and/or diarrhoea or other gastrointestinal conditions can affect the absorption of oral 

hormonal contraceptives, such as birth control pills, and may reduce their effectiveness.Therefore, 
if experiencing these, talk to your doctor to discuss an alternative more appropriate method of 
contraception.

- Tell your doctor or pharmacist immediately if you become pregnant or think you may be pregnant 
during treatment with Ofev. 

Breast-feeding
Do not breast-feed during the treatment with Ofev since there may be a risk of harm to the breast-fed 
child.

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

Ofev contains soya lecithin
If you are allergic to soya or peanut, do not take this medicine (see section 2).

3. How to take Ofev

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

The recommended dose is one capsule of 100 mg twice daily (a total of 200 mg per day). Take the 
capsules twice daily approximately 12 hours apart at about the same time every day, for example one 
capsule in the morning and one capsule in the evening. This ensures that a steady amount of 
nintedanib is maintained in your blood stream. Swallow the whole capsules with water and do not 
chew or crush the capsules. It is recommended that you take the capsules with food, i.e. during or 
immediately before or after a meal.

Do not take more than the recommended dose of two Ofev 100 mg capsules per day.



43

If you do not tolerate the recommended dose of two Ofev 100 mg capsules per day (see possible side 
effects in section 4) your doctor may advise you to stop taking this medicine. Do not reduce the dose 
or stop the treatment by yourself without consulting your doctor first.

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

If you forget to take Ofev
Do not take two capsules together if you have forgotten to take your earlier dose. You should take 
your next 100 mg dose of Ofev as planned at the next scheduled time recommended by your doctor or 
pharmacist.

If you stop taking Ofev
Do not stop taking Ofev 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 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 Ofev:

Diarrhoea (very common, may affect more than 1 in 10 people):
Diarrhoea may lead to dehydration: a loss of fluid and important salts (electrolytes, such as sodium or 
potassium) from 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.

The following other side effects were observed during treatment with this medicine.
Talk to your doctor if you get any side effects.

Idiopathic pulmonary fibrosis (IPF)

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Pain in the lower body (abdomen) 
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Vomiting
- Loss of appetite
- Weight loss
- Bleeding
- Rash
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Pancreatitis
- Inflammation of the large bowel
- Serious liver problems
- Low platelet count (thrombocytopenia)
- High blood pressure (hypertension)
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin



44

- Itching
- Heart attack
- Hair loss (alopecia)

Not known (cannot be estimated from the available data)
- Renal failure
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms 

and artery dissections)

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

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Vomiting
- Loss of appetite
- Pain in the lower body (abdomen)
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Weight loss
- High blood pressure (hypertension)
- Bleeding
- Serious liver problems
- Rash
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Pancreatitis
- Inflammation of the large bowel
- Low platelet count (thrombocytopenia)
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin
- Itching
- Heart attack
- Hair loss (alopecia)

Not known (cannot be estimated from the available data)
- Renal failure
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms 

and artery dissections)

Systemic sclerosis associated interstitial lung disease (SSc-ILD)

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Vomiting
- Pain in the lower body (abdomen) 
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Bleeding
- High blood pressure (hypertension)
- Loss of appetite
- Weight loss
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Inflammation of the large bowel



45

- Serious liver problems
- Renal failure
- Low platelet count (thrombocytopenia)
- Rash
- Itching

Not known (cannot be estimated from the available data)
- Heart attack
- Pancreatitis
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms 

and artery dissections)
- Hair loss (alopecia)

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 Ofev

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 the blister. The expiry 
date refers to the last day of that month.

Do not store Ofev 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 Ofev contains 
- The active substance is nintedanib. Each capsule contains 100 mg nintedanib (as esilate).
- The other ingredients are:

Capsule fill: Triglycerides, medium-chain, hard fat, soya lecithin (E322) (see section 2)
Capsule shell: Gelatin, glycerol (85%), titanium dioxide (E171), iron oxide red (E172), iron 

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

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

Two pack-sizes of Ofev 100 mg capsules are available:
- 30 x 1 soft capsules in aluminium/aluminium perforated unit dose blisters 
- 60 x 1 soft capsules in aluminium/aluminium perforated unit dose blisters 

Not all pack-sizes may be marketed.

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


46

Marketing Authorisation Holder

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

Manufacturer

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

Boehringer Ingelheim France
100-104 Avenue de France
75013 Paris
France



47

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 5 2595942

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



48

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


49

Package leaflet: Information for the patient

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

1. What Ofev is and what it is used for

Ofev contains the active substance nintedanib, a medicine belonging to the class of so-called tyrosine 
kinase inhibitors, and it is used for the treatment of idiopathic pulmonary fibrosis (IPF), other chronic 
fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis 
associated interstitial lung disease (SSc-ILD) in adults.

Idiopathic pulmonary fibrosis (IPF)
IPF is a condition in which the tissue in your lungs becomes thickened, stiff and scarred over time. As 
a result, scarring reduces the ability to transfer oxygen from the lungs into the bloodstream and it 
becomes difficult to breathe deeply. Ofev helps to reduce scarring and stiffening of the lungs.

Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype
Besides IPF, there are other conditions in which the tissue in your lungs becomes thickened, stiff, and 
scarred over time (lung fibrosis) and keeps worsening (progressive phenotype). Examples of these 
conditions are hypersensitivity pneumonitis, autoimmune ILDs (e.g. rheumatoid arthritis associated 
ILD), idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, 
and other ILDs. Ofev helps to reduce further scarring and stiffening of the lungs.

Systemic sclerosis associated interstitial lung disease (SSc-ILD)
Systemic sclerosis (SSc), also known as scleroderma, is a rare chronic autoimmune disease that affects 
connective tissue in many parts of the body. SSc causes fibrosis (scarring and stiffening) of the skin 
and other internal organs such as the lungs. When the lungs are affected by fibrosis, it is called 
interstitial lung disease (ILD), and so the condition is called SSc-ILD. Fibrosis in the lungs reduces the 
ability to transfer oxygen into the bloodstream, and breathing capacity is reduced. Ofev helps to reduce 
further scarring and stiffening of the lungs.



50

2. What you need to know before you take Ofev

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

(listed in section 6).

Warnings and precautions 
Talk to your doctor or pharmacist before taking Ofev,
- if you have or ever had liver problems, 
- if you have or ever had problems with your kidney,
- if you have or ever had bleeding problems,
- if you take blood-thinning medicines (such as warfarin, phenprocoumon or heparin) to prevent 

blood clotting,
- if you take pirfenidone as this may increase the risk of having diarrhoea, nausea, vomiting and liver 

problems,
- if you have or ever had problems with your heart (for example a heart attack),
- if you have recently had surgery. Nintedanib may affect the way your wounds heal. Therefore, your 

treatment with Ofev will usually be stopped for a while if you are having a surgery. Your doctor 
will decide when to resume your treatment with this medicine.

- if you have high blood pressure,
- if you have abnormally high blood pressure in the blood vessels of the lungs (pulmonary

hypertension),
- 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 do some blood tests, for example to check your liver 
function. Your doctor will discuss the results of these tests with you and decide whether you may 
receive Ofev.

Inform your doctor immediately while taking this medicine, 
- if you get diarrhoea. Treating diarrhoea early 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 have severe pain in your stomach, 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’). Also, tell your doctor if you had peptic ulcers or diverticular disease in the past, or 
are concomitantly treated with anti-inflammatory drugs (NSAIDs) (used to treat pain relief and 
swelling) or steroids (used for inflammation and allergies), as this may increase this risk;

- if you have a combination of severe pain or cramping in your stomach, red blood in your stool or 
diarrhea as these could be symptoms of a bowel inflammation from inadequate blood supply;

- if you have pain, swelling, reddening, warmth of a limb as this could be symptoms of a blood clot 
in one of your veins (a type of blood vessel);

- if you have 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 you have any major bleeding.

Children and adolescents
Ofev should not be taken by children and adolescents under 18 years of age.



51

Other medicines and Ofev
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.

Ofev can interact with certain other medicines. The following medicines are examples that may 
increase the levels of nintedanib in your blood, and hence may increase the risk for side effects (see 
section 4):
- a medicine used to treat fungal infections (ketoconazole)
- a medicine used to treat bacterial infections (erythromycin)
- a medicine that affects your immune system (cyclosporine)

The following medicines are examples that may lower the levels of nintedanib in your blood and thus 
may reduce the effectiveness of Ofev:
- an antibiotic used to treat tuberculosis (rifampicin)
- medicines to treat seizures (carbamazepine, phenytoin)
- a herbal medicine to treat depression (St. John’s Wort)

Pregnancy and breast-feeding
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.

Pregnancy
Do not take this medicine during pregnancy, as it can harm your unborn baby and cause birth defects.

You must have a pregnancy test done to ensure you are not pregnant before starting treatment with 
Ofev. Please talk to your doctor.

Contraception
- Women who can become pregnant must use a highly effective method of birth control to prevent 

pregnancy when they start taking Ofev while they are taking Ofev and for at least 3 months after 
stopping treatment.

- You should discuss the most appropriate methods of contraception for you with your doctor.
- Vomiting and/or diarrhoea or other gastrointestinal conditions can affect the absorption of oral 

hormonal contraceptives, such as birth control pills, and may reduce their effectiveness. Therefore,
if experiencing these, talk to your doctor to discuss an alternative more appropriate method of 
contraception.

- Tell your doctor or pharmacist immediately if you become pregnant or think you may be pregnant 
during treatment with Ofev.

Breast-feeding
Do not breast-feed during the treatment with Ofev since there may be a risk of harm to the breast-fed 
child.

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

Ofev contains soya lecithin
If you are allergic to soya or peanut, do not take this medicine (see section 2).

3. How to take Ofev

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



52

The recommended dose is one capsule of 150 mg twice daily (a total of 300 mg per day). Take the 
capsules twice daily approximately 12 hours apart at about the same time every day, for example one 
capsule in the morning and one capsule in the evening. This ensures that a steady amount of 
nintedanib is maintained in your blood stream. Swallow the whole capsules with water and do not 
chew or crush the capsules. It is recommended that you take the capsules with food, i.e. during or 
immediately before or after a meal.

Do not take more than the recommended dose of two Ofev 150 mg capsules per day.

If you do not tolerate the recommended dose of two Ofev 150 mg capsules per day (see possible side 
effects in section 4) your doctor may reduce the daily dose of Ofev. Do not reduce the dose or stop the 
treatment by yourself without consulting your doctor first.

Your doctor may reduce your recommended dose to two times 100 mg per day (a total of 200 mg per 
day). In this case your doctor will prescribe Ofev 100 mg capsules for your treatment. Do not take 
more than the recommended dose of two Ofev 100 mg capsules per day if your daily dose was reduced 
to 200 mg per day.

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

If you forget to take Ofev
Do not take two capsules together if you have forgotten to take your earlier dose.You should take your 
next 150 mg dose of Ofev as planned at the next scheduled time recommended by your doctor or 
pharmacist.

If you stop taking Ofev
Do not stop taking Ofev 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 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 Ofev:

Diarrhoea (very common, may affect more than 1 in 10 people):
Diarrhoea may lead to dehydration: a loss of fluid and important salts (electrolytes, such as sodium or 
potassium) from 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.

The following other side effects were observed during treatment with this medicine. 
Talk to your doctor if you get any side effects.

Idiopathic pulmonary fibrosis (IPF)

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Pain in the lower body (abdomen) 
- Abnormal liver test results.

Common side effects (may affect up to 1 in 10 people)
- Vomiting



53

- Loss of appetite
- Weight loss
- Bleeding
- Rash
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Pancreatitis
- Inflammation of the large bowel
- Serious liver problems
- Low platelet count (thrombocytopenia)
- High blood pressure (hypertension)
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin 
- Itching
- Heart attack
- Hair loss (alopecia)

Not known (cannot be estimated from the available data)
- Renal failure
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms 

and artery dissections)

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

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Vomiting
- Loss of appetite
- Pain in the lower body (abdomen)
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Weight loss
- High blood pressure (hypertension)
- Bleeding
- Serious liver problems
- Rash
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Pancreatitis
- Inflammation of the large bowel
- Low platelet count (thrombocytopenia)
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin
- Itching
- Heart attack
- Hair loss (alopecia)

Not known (cannot be estimated from the available data)
- Renal failure
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms 

and artery dissections)



54

Systemic sclerosis associated interstitial lung disease (SSc-ILD)

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Vomiting
- Pain in the lower body (abdomen) 
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Bleeding
- High blood pressure (hypertension)
- Loss of appetite
- Weight loss
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Inflammation of the large bowel
- Serious liver problems
- Renal failure
- Low platelet count (thrombocytopenia)
- Rash
- Itching

Not known (cannot be estimated from the available data)
- Heart attack
- Pancreatitis
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms 

and artery dissections)
- Hair loss (alopecia)

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 Ofev

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 the blister. The expiry 
date refers to the last day of that month.

Do not store Ofev 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.

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


55

6. Contents of the pack and other information

What Ofev contains
- The active substance is nintedanib. Each capsule contains 150 mg nintedanib (as esilate).
- The other ingredients are:

Capsule fill:  Triglycerides, medium-chain, hard fat, soya lecithin (E322) (see section 2)
Capsule shell:  Gelatin, glycerol (85%), titanium dioxide (E171), iron oxide red (E172), iron 

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

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

Two pack-sizes of Ofev 150 mg capsules are available:
- 30 x 1 soft capsules in aluminium/aluminium perforated unit dose blisters 
- 60 x 1 soft capsules in aluminium/aluminium perforated unit dose blisters 

Not all pack-sizes may be marketed.

Marketing Authorisation Holder

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

Manufacturer

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

Boehringer Ingelheim France
100-104 Avenue de France
75013 Paris
France



56

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 5 2595942

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



57

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


58

ANNEX IV

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S)



59

Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for nintedanib (respiratory 
indication), the scientific conclusions of CHMP are as follows: 

In view of available data on ischaemic colitis from clinical trials, literature, signal assessment 
performed by WHO, plausible mechanism of action and high number of fatal cases, the PRAC 
considers that a causal relationship between nintedanib (for respiratory indications) and ischaemic 
colitis is at least a reasonable possibility. The biologic plausibility of an association between 
nintedanib and ischaemic colitis based upon its inhibitory action of the VEGF-receptor appears 
reasonable. The PRAC concluded that the product information of nintedanib for respiratory 
indications (Ofev) should be amended accordingly.

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 (respiratory indication) the CHMP is of the 
opinion that the benefit-risk balance of the medicinal product(s) containing nintedanib (respiratory 
indication) 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 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)