4.1. Therapeutic indications

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

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

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

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

4.2. Posology and method of administration

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

Posology

Adults

Idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis associated interstitial lung disease (SSc-ILD)

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.

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 nintedanib (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. Nintedanib treatment may be resumed at the full dose (150 mg twice daily in adult patients) or a reduced dose (100 mg twice daily in adult patients). If an adult patient does not tolerate 100 mg twice daily, treatment with nintedanib 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 in adult patients) or at the full dose (150 mg twice daily in adult patients). In case of persisting severe diarrhoea, nausea and/or vomiting despite symptomatic treatment, therapy with nintedanib should be discontinued (see section 4.4).

In case of interruptions due to aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations > 3 x upper limit of normal (ULN), once transaminases have returned to baseline values, treatment with nintedanib may be reintroduced at a reduced dose (100 mg twice daily in adult patients) which subsequently may be increased to the full dose (150 mg twice daily in adult patients) (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 in elderly patients. 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 adult patients with mild hepatic impairment (Child Pugh A), the recommended dose of Nintedanib capsules 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 Nintedanib capsules is not recommended (see section 5.2).

Paediatric population

Nintedanib should not be used in children (see section 4.8 and 5.1).

Non-small cell lung cancer (NSCLC)

The recommended dose of nintedanib is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21-day docetaxel treatment cycle.

Nintedanib must not be taken on the same day of docetaxel chemotherapy administration (= day 1). If a dose of nintedanib is missed, administration should resume at the next scheduled time at the recommended dose. The individual daily doses of nintedanib should not be increased beyond the recommended dose to make up for missed doses. The recommended maximum daily dose of 400 mg should not be exceeded.

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

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

Dose adjustments

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

Nintedanib treatment may be resumed at a reduced dose. Dose adjustments in 100 mg steps per day (i.e. a 50 mg reduction per dosing) based on individual safety and tolerability are recommended as described in Table 1 and Table 2.

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

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

CTCAE* Adverse reaction

Dose adjustment

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

OR

Diarrhoea ≥ grade 3 despite anti-diarrhoeal treatment

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

Vomiting ≥ grade 2

AND/OR

Nausea ≥ grade 3 despite anti-emetic treatment

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

* CTCAE: Common Terminology Criteria for Adverse Events

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

AST / ALT and bilirubin elevations

Dose adjustment

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

OR

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

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

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

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

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase

ALKP: Alkaline phosphatase; ULN: Upper limit normal

Special populations

Elderly patients (≥ 65 years)

No overall differences in safety and efficacy were observed for elderly patients. In the pivotal trial 1199.13, 85 patients (12.9% of the patients with adenocarcinoma histology) were ≥ 70 years of age (median age: 72 years, range: 70-80 years) (see section 5.1). No adjustment of the initial dosing is required in elderly patients (see section 5.2).

Race and body weight

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

Renal impairment

Less than 1% of a single dose of nintedanib is excreted via the kidney (see section 5.2). Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (< 30 mL/min creatinine clearance).

Hepatic impairment

Nintedanib is predominantly eliminated via biliary/faecal excretion (> 90%). Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B; see section 5.2). No adjustment of the starting dose is needed for patients with mild hepatic impairment (Child Pugh A) based on clinical data. Limited safety data available from 9 patients with moderate hepatic impairment (Child Pugh B) are insufficient to characterize this population. The safety, efficacy and pharmacokinetics of nintedanib have not been investigated in patients with severe hepatic impairment (Child Pugh C). Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with nintedanib is not recommended (see sections 4.4 and 5.2).

Paediatric population

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

Method of administration

Nintedanib is for oral use. The capsules should be taken with food, swallowed whole with water, and should not be chewed as the dosage form is a soft gelatin capsule containing liquid suspension. The capsule should not be opened or crushed (see section 6.6). Nintedanib capsules may be taken with a small amount (one teaspoonful) of cold or room temperature soft food, such as apple sauce or chocolate pudding, and must be swallowed unchewed immediately to ensure the capsule stays intact.

4.3. Contraindications

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

For patients with IPF, ILD or SSc-ILD pregnancy is contraindicated (see section 4.6).

4.4. Special warnings and precautions for use

Idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis associated interstitial lung disease (SSc-ILD)

Gastrointestinal disorders

Diarrhoea

In the clinical trials, 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. Nintedanib treatment may be resumed at a reduced dose or at the full dose (see section 4.2). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with nintedanib 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 Nintedanib in up to 2.1% of patients and vomiting led to discontinuation of nintedanib 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 or at the full dose (see section 4.2 Dose adjustments). In case of persisting severe symptoms therapy with nintedanib should be discontinued.

Hepatic function

The safety and efficacy of nintedanib has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore, treatment with nintedanib 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). Adult patients with mild hepatic impairment (Child Pugh A) should be treated with a reduced dose of nintedanib (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 nintedanib. 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 > 3 x ULN are measured, dose reduction or interruption of the therapy with nintedanib is recommended and the patient should be monitored closely. Once transaminases have returned to baseline values, treatment with nintedanib may be resumed at the full dose or reintroduced at a reduced dose which subsequently may be increased to the full dose (see section 4.2 Dose adjustments). If any liver test elevations are associated with clinical signs or symptoms of liver injury, e.g. jaundice, treatment with nintedanib should be permanently discontinued. Alternative causes of the liver enzyme elevations should be investigated.

Adult 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.

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 nintedanib 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 in adult patients, arterial thromboembolic events were infrequently reported (nintedanib 2.5% versus placebo 0.7% for INPULSIS; nintedanib 0.9% versus placebo 0.9% for INBUILD; nintedanib 0.7% versus placebo 0.7% for SENSCIS). In the INPULSIS trials, a higher percentage of patients experienced myocardial infarctions in the nintedanib group (1.6%) compared to the placebo group (0.5%), while adverse events reflecting ischaemic heart disease were balanced between the nintedanib and placebo groups. In the INBUILD trial, myocardial infarction was observed with low frequency: nintedanib 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 nintedanib 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 nintedanib, 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 in adult patients, 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. nintedanib should only be initiated at least 4 weeks after abdominal surgery. Therapy with nintedanib should be permanently discontinued in patients who develop gastrointestinal perforation or ischaemic colitis. Exceptionally, nintedanib can be reintroduced after complete resolution of ischaemic colitis and careful assessment of patient's condition and other risk factors.

Nephrotic range proteinuria and thrombotic microangiopathy

Very few cases of nephrotic range proteinuria with or without renal function impairment have been reported post-marketing. Histological findings in individual cases were consistent with glomerular microangiopathy with or without renal thrombi. Reversal of the symptoms has been observed after nintedanib was discontinued, with residual proteinuria in some cases. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.

VEGF pathway inhibitors have been associated with thrombotic microangiopathy (TMA), including very few case reports for nintedanib. If laboratory or clinical findings associated with TMA occur in a patient receiving nintedanib, treatment with nintedanib should be discontinued and thorough evaluation for TMA should be completed.

Posterior reversible encephalopathy syndrome (PRES)

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

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

If PRES is suspected, nintedanib treatment must be discontinued. Reinitiating nintedanib therapy in patients previously experiencing PRES is not known and should be left to the physician's recommendation.

Hypertension

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

Pulmonary hypertension

Data on the use of nintedanib 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.

Nintedanib 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 nintedanib 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.

Non-small cell lung cancer (NSCLC)

Gastrointestinal disorders

Diarrhoea was the most frequently reported gastro-intestinal adverse reaction and appeared in close temporal relationship with the administration of docetaxel (see section 4.8). In the clinical trial LUME-Lung 1 (see section 5.1), the majority of patients had mild to moderate diarrhoea.

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

Nausea and vomiting, mostly of mild to moderate severity, were frequently reported gastrointestinal adverse reactions (see section 4.8). Interruption, dose reduction or discontinuation of therapy with nintedanib (see section 4.2) may be required despite appropriate supportive care. Supportive care for nausea and vomiting may include medicinal products with anti-emetic properties, e.g. glucocorticoids, anti-histamines or 5-HT3 receptor antagonists and adequate hydration.

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

Neutropenia and sepsis

A higher frequency of neutropenia of CTCAE grade ≥ 3 was observed in patients treated with nintedanib in combination with docetaxel as compared to treatment with docetaxel alone.

Subsequent complications such as sepsis or febrile neutropenia have been observed (including fatal cases).

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

Hepatic function

Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A; see sections 4.2 and 5.2). Limited safety data are available in 9 patients with hepatocellular carcinoma and moderate hepatic impairment classified as Child Pugh B. Although no unexpected safety findings were reported in these patients, the data are insufficient to support a recommendation for treatment of patients with moderate hepatic impairment. The efficacy of nintedanib has not been investigated in patients with moderate hepatic impairment (Child Pugh B). The safety, efficacy and pharmacokinetics of nintedanib have not been studied in patients with severe hepatic impairment (Child Pugh C). Treatment with nintedanib is not recommended in patients with moderate or severe hepatic impairment (see section 4.2).

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

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

If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with nintedanib may be required (see section 4.2). Alternative causes of the liver enzyme elevations should be investigated and respective action should be taken as necessary. In case of specific changes in liver values (AST/ALT > 3 x ULN; total bilirubin ≥ 2 x ULN and ALKP < 2 x ULN) treatment with nintedanib should be interrupted. Unless there is an alternative cause established, nintedanib should be permanently discontinued (see section 4.2).

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

Renal function

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

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

Haemorrhage

VEGFR inhibition might be associated with an increased risk of bleeding. In the clinical trial (LUME-Lung 1; see section 5.1) with nintedanib, the frequency of bleeding in both treatment arms was comparable (see section 4.8). Mild to moderate epistaxis represented the most frequent bleeding event. The majority of fatal bleeding events were tumour-associated. There were no imbalances of respiratory or fatal bleedings and no intracerebral bleeding was reported.

Patients with recent pulmonary bleeding (> 2.5 mL of red blood) as well as patients with centrally located tumours with radiographic evidence of local invasion of major blood vessels or radiographic evidence of cavitary or necrotic tumours have been excluded from clinical trials. Therefore, it is not recommended to treat these patients with nintedanib.

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

Therapeutic anticoagulation

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

Brain metastasis

-Stable brain metastasis

No increased frequency of cerebral bleeding in patients with adequately pre-treated brain metastases which were stable for ≥ 4 weeks before start of treatment with nintedanib was observed. However, such patients should be closely monitored for signs and symptoms of cerebral bleeding.

-Active brain metastasis

Patients with active brain metastasis were excluded from clinical trials and are not recommended for treatment with nintedanib.

Venous thromboembolism

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

Arterial thromboembolic events

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

Aneurysms and artery dissections

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

Gastrointestinal perforations and ischaemic colitis

The frequency of gastrointestinal perforation was comparable between the treatment arms in the clinical trial. However, based on the mechanism of action patients treated with nintedanib may have an increased risk of gastrointestinal perforations. Cases of gastrointestinal perforations and ischaemic colitis, some of which were fatal, have been reported in the post-marketing period under nintedanib. Particular caution should be exercised when treating patients with previous abdominal surgery or a recent history of a hollow organ perforation. nintedanib should therefore only be initiated at least 4 weeks after major surgery. Therapy with nintedanib should be permanently discontinued in patients who develop gastrointestinal perforation. In patients who develop ischaemic colitis nintedanib should be discontinued, and exceptionally, nintedanib can be reintroduced after complete resolution of ischaemic colitis and careful assessment of patient's condition and other risk factors.

Nephrotic range proteinuria

Very few cases of nephrotic range proteinuria have been reported post-marketing. Histological findings in individual cases were consistent with glomerular microangiopathy with or without renal thrombi. Reversal of symptoms has been observed after nintedanib was discontinued. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.

Posterior reversible encephalopathy syndrome (PRES)

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

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

If PRES is suspected, nintedanib treatment must be discontinued. Reinitiating nintedanib therapy in patients previously experiencing PRES is not known and should be left to the physician's recommendation.

Wound healing complication

Based on the mechanism of action nintedanib may impair wound healing. No increased frequency of impaired wound healing was observed in the LUME-Lung 1 trial. No dedicated trials investigating the effect of nintedanib on wound healing were performed. Treatment with nintedanib should therefore only be initiated or – in case of perioperative interruption – resumed based on clinical judgement of adequate wound healing.

Effect on QT interval

No QT prolongation was observed for nintedanib in the clinical trial program (see section 5.1). As several other tyrosine kinase inhibitors are known to exert an effect on QT, caution should be exercised when administering nintedanib in patients who may develop QTc prolongation.

Special populations

In trial 1199.13 (LUME-Lung 1), there was a higher frequency of SAEs in patients treated with nintedanib plus docetaxel with a body weight of less than 50 kg compared to patients with a weight ≥ 50 kg; however the number of patients with a body weight of less than 50 kg was small. Therefore close monitoring is recommended in patients weighing < 50 kg.

4.5. Interaction with other medicinal products and other forms of interaction

P-glycoprotein (P-gp)

Nintedanib is a substrate of P-gp (see section 5.2). Co-administration with the potent P-gp inhibitor ketoconazole increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on Cmax in a dedicated drug-drug interaction study. In a drug-drug interaction study with the potent P-gp inducer rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on Cmax upon co-administration with rifampicin compared to administration of nintedanib alone. If co-administered with nintedanib, potent P-gp inhibitors (e.g. ketoconazole, 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 nintedanib (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.

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).

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

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 nintedanib and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of nintedanib. 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

Patients with IPF, ILD, SSc-ILD

There is no information on the use of nintedanib 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 nintedanib and during treatment as appropriate.

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

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

Patients with NSCLC

There is no information on the use of nintedanib 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 should not be used during pregnancy unless the clinical condition requires treatment. Pregnancy testing should be conducted at least prior to treatment with nintedanib.

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

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

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 nintedanib.

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). There are no human data on potential effects of nintedanib on female fertility available.

4.7. Effects on ability to drive and use machines

Nintedanib 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 nintedanib.

4.8. Undesirable effects

Idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis associated interstitial lung disease (SSc-ILD)

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.

Tabulated list of adverse reactions

Table 4 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 4: 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

Alopecia

Uncommon

Uncommon

Not known

Renal and urinary disorders

Renal failure (see section 4.4)

Not known

Not known

Uncommon

Proteinuria

Uncommon

Uncommon

Not known

Nervous system disorders

Headache

Common

Common

Common

Posterior reversible encephalopathy syndrome

Not known

Not known

Not known

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 5:

Table 5: Diarrhoea in clinical trials over 52 weeks

INPULSIS

INBUILD

SENSCIS

Placebo

Nintedanib

Placebo

Nintedanib

Placebo

Nintedanib

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 nintedanib dose reduction

0%

10.7%

0.9%

16.0%

1.0%

22.2%

Diarrhoea leading to nintedanib 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 nintedanib and placebo, respectively. In the INBUILD trial, liver enzyme elevations were reported in 22.6% versus 5.7% of patients treated with nintedanib and placebo, respectively. In the SENSCIS trial, liver enzyme elevations were reported in 13.2% versus 3.1% of patients treated with nintedanib 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 nintedanib or comparable between the treatment arms (nintedanib 10.3% versus placebo 7.8% for INPULSIS; nintedanib 11.1% versus placebo 12.7% for INBUILD; nintedanib 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 (nintedanib 1.3% versus placebo 1.4% for INPULSIS; nintedanib 0.9% versus placebo 1.5% for INBUILD; nintedanib 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).

Proteinuria

In clinical trials, the frequency of patients who experienced proteinuria was low and comparable between the treatment arms (nintedanib 0.8% versus placebo 0.5% for INPULSIS; nintedanib 1.5% versus placebo 1.8% for INBUILD; nintedanib 1.0% versus placebo 0.0% for SENSCIS). Nephrotic syndrome has not been reported in clinical trials. Very few cases of nephrotic range proteinuria with or without renal function impairment have been reported post-marketing. Histological findings in individual cases were consistent with glomerular microangiopathy with or without renal thrombi. Reversal of the symptoms has been observed after nintedanib was discontinued, with residual proteinuria in some cases. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome (see section 4.4).

Paediatric population

There are limited safety data for nintedanib in paediatric patients.

A total of 39 patients aged 6 to 17 years were treated in a randomised, double-blind, placebo- controlled trial of 24 weeks duration, followed by open label treatment with nintedanib of variable duration (see section 5.1). Consistent with the safety profile seen in adult patients with IPF, other chronic fibrosing ILDs with progressive phenotype and SSc-ILD, the most frequently reported adverse reactions with nintedanib during placebo-controlled period were diarrhoea (38.5%), vomiting (26.9%), nausea (19.2%), abdominal pain (19.2%), and headache (11.5%).

Hepatobiliary disorders reported with nintedanib during placebo-controlled period were liver injury (3.8%) and increased liver function test (3.8%). Due to limited data, it is uncertain if the risk for drug-induced liver injury is similar in children as compared to adults (see section 4.4).

Based on preclinical findings, bone, growth and teeth development were monitored as potential risks in the paediatric clinical trial (see section 5.3). The potential impact on growth and tooth development is unknown (see section 5.1).

Long term safety data in paediatric patients are not available. There are uncertainties on the potential impact on growth, tooth development, puberty, and the risk of liver injury.

Non-small cell lung cancer (NSCLC)

Summary of the safety profile

The safety data provided in the sections below are based on the global, double-blind randomised pivotal phase 3 trial 1199.13 (LUME-Lung 1) comparing treatment with nintedanib plus docetaxel against placebo plus docetaxel in patients with locally advanced, or metastatic, or recurrent NSCLC after first-line chemotherapy and based on data observed during the post-marketing period. The most frequently reported adverse drug reactions (ADRs) specific for nintedanib were diarrhoea, increased liver enzyme values (ALT and AST) and vomiting. Table 6 provides a summary of the adverse reactions by System Organ Class (SOC). For the management of selected adverse reactions, see section 4.4. Information about selected adverse reactions observed from the LUME-Lung 1 trial are described below.

Tabulated list of adverse reactions

Table 6 summarizes the frequencies of adverse drug reactions that were reported in the pivotal trial LUME-Lung 1 for patients with NSCLC of adenocarcinoma tumour histology (n = 320) or from the post-marketing period. The following terms are used to rank the ADRs by frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping adverse reactions are presented in order of decreased seriousness.

Table 6: Summary of ADRs per frequency category

System Organ Class

Very common

(≥ 1/10)

Common

(≥ 1/100 < 1/10)

Uncommon

(≥ 1/1 000 < 1/100)

Not known

Infections and infestations

Febrile neutropenia, Abscesses, Sepsis

Blood and lymphatic system disorders

Neutropenia (includes febrile neutropenia)

Thrombocytope­nia

Metabolism and nutrition disorders

Decreased appetite, Electrolyte imbalance

Dehydration, Weight decreased

Nervous system disorders

Peripheral neuropathy

Headache1)

Posterior reversible encephalopathy syndrome

Cardiac disorders

Myocardial infarction (see section 4.4)

Vascular disorders

Bleeding1) (see section 4.4)

Venous thromboembo­lism3), Hypertension

Aneurysms and artery dissections

Gastrointestinal disorders

Diarrhoea, Vomiting, Nausea, Abdominal pain

Perforation1) Pancreatitis2)

Colitis

Hepatobiliary disorders

Alanine aminotransferase (ALT) increased, Aspartate aminotransferase (AST) increased, Blood alkaline phosphatase (ALKP) increased

Hyperbilirubinaemia, Gamma-glutamyltransferase (GGT) increased

Drug-induced liver injury

Skin and subcutaneous tissue disorders

Mucositis (including stomatitis), Rash, Alopecia1)

Pruritus

Renal and urinary disorders

Proteinuria1)

Renal failure (see section 4.4)

1) In clinical trials the frequency was not increased in patients treated with nintedanib plus docetaxel as compared to placebo plus docetaxel.

2) Events of pancreatitis have been reported in patients taking nintedanib for the treatment of IPF and NSCLC. The majority of these events were reported for patients in the IPF indication.

3) Cases of pulmonary embolism have been reported.

Description of selected adverse reactions

Diarrhoea

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

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

Liver enzyme elevations and hyperbilirubinaemia

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

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

Neutropenia, febrile neutropenia and sepsis

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

Bleeding

In the post-marketing period non-serious and serious bleeding events, some of which fatal, have been reported, including patients with or without anticoagulant therapy or other medicinal products that could cause bleeding. Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous system organs, with the most frequent being respiratory (see also section 4.4).

Perforation

As expected via its mechanism of action perforation might occur in patients treated with nintedanib. However, the frequency of patients with gastrointestinal perforation was low.

Peripheral neuropathy

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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