nintedanib: prescribing information – dosing, contraindications, interactions, side effects

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 children and adolescents from 6 to 17 years old for the treatment of clinically significant, progressive fibrosing interstitial lung diseases (ILDs) (see section 4.2 and 5.1).

Ofev is indicated in adults, adolescents and children aged 6 years and older for the treatment of

systemic sclerosis associated interstitial lung disease (SSc-ILD).

Adults: Treatment should be initiated by physicians experienced in the management of diseases for which Ofev is approved.
Paediatric patients: Treatment should be initiated only after involvement of a multidisciplinary team (physicians, radiologists, pathologists) experienced in the diagnosis and treatment of fibrosing interstitial lung diseases (ILDs).

Posology

Adults
- Idiopathic pulmonary fibrosis (IPF)
- Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype
- 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 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 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 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 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 Ofev should be discontinued (see section 4.4).

In case of interruptions due to aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations > 3× 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 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).

For specific dose reduction recommendations for the management of adverse reactions in paediatric population, see Table 1.

Children and adolescents from 6 to 17 years old
- Treatment of clinically significant, progressive fibrosing interstitial lung diseases (ILDs)
- Treatment of systemic sclerosis associated interstitial lung disease (SSc-ILD)

Growth must be regularly monitored, and evaluation of epiphyseal growth plate alteration via annual bone imaging is recommended in patients with open epiphyses. Treatment interruption should be considered in patients who develop signs of growth impairment or epiphyseal growth plates alterations (see sections 4.4 and 4.8).

Oral dental examination must regularly be performed at least every 6 months until development of dentition is completed (see sections 4.4 and 4.8).

The recommended dose of Ofev for paediatric patients aged 6 to 17 years of age is based on the patient’s weight and is administered twice daily, approximately 12 hours apart (see Table 1). The dose should be adjusted according to weight as treatment progresses.

Table 1:
Ofev dose and reduced dose recommendation in milligrams (mg) by body weight in kilograms (kg) for paediatric patients aged 6 years to 17 years old

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 adult and paediatric patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in adult and paediatric 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 Ofev is 100 mg twice daily approximately 12 hours apart. In paediatric patients with mild hepatic impairment (Child Pugh A), a reduced starting dose is recommended (see table 1). In adult and paediatric 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 adult and paediatric patients with hepatic impairment classified as Child Pugh B and C. Treatment of adult and paediatric patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Ofev is not recommended (see section 5.2).

Paediatric population
Weight range
Ofev dose
Ofev reduced dose*

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

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 2 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 2:
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
Nervous system disorders
Headache
Common
Common
Common
Posterior reversible encephalopathy syndrome
Not known
Not known
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

Frequency
System Organ Class preferred term
Idiopathic pulmonary fibrosis
Other chronic fibrosing ILDs with a progressive phenotype
Systemic sclerosis associated interstitial lung disease
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

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 3:

Table 3:
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).

Proteinuria
In clinical trials, the frequency of patients who experienced proteinuria was low and comparable between the treatment arms (Ofev 0.8% versus placebo 0.5% for INPULSIS; Ofev 1.5% versus placebo 1.8% for INBUILD; Ofev 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 Ofev 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 pediatric 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 4.2, 4.4 and 5.3).

The percentage of patients with treatment-emergent pathological findings of epiphyseal growth plate, which was similar across the treatment groups at week 24 (7.7% in both treatment groups). Up to week 52, the percentage of patients with pathological findings was nintedanib/nintedanib: 11.5% and placebo/nintedanib: 15.4%.

The percentage of patients with treatment-emergent pathological findings on dental examination or imaging, which was 46.2% in the nintedanib group and 38.5% in the placebo group up to week 24. Up to week 52, the percentage of patients with pathological findings was nintedanib/nintedanib: 50.0% and placebo/nintedanib: 46.2%.

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.

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.

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. Ofev 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 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 or at the full dose (see section 4.2 Dose adjustments). 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). Adult 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 > 3× 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 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 Ofev 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 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 in adult patients, 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 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. 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.

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

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 (see section 4.3). Patients with known allergy to peanut protein carry an enhanced risk for severe reactions to soya preparations.

Paediatric population
Data on the use of nintedanib in paediatric patients is limited to a small subset of fibrosing interstitial lung diseases (see section 5.1). This subset does not cover all aetiologies associated with progressive fibrosing interstitial lung disease in paediatric patients.

There is greater uncertainty regarding the magnitude of treatment benefit in paediatric patients than in adults.

The above precautions for adult patients must also be followed for paediatric patients.

For specific dose reduction recommendations in paediatric population, see Table 1.

Particularities for the paediatric population are detailed below:

Bone development and growth
Reversible epiphyseal growth plate alterations were observed in preclinical studies (see section 5.3). In the paediatric clinical trial, significant reductions in growth rate were not observed while receiving nintedanib. However, long term safety data in paediatric patients are not available.
Growth must be regularly monitored, and evaluation of epiphyseal growth plate alteration via annual bone imaging is recommended in patients with open epiphyses. Treatment interruption should be considered in patients who develop signs of growth impairment or epiphyseal growth plates alterations.

Tooth development disorders
Tooth development disorders were observed in preclinical studies (see section 5.3). In the paediatric clinical trial, the risk of tooth development disorders was not confirmed.
As a precautionary measure, oral dental examination must regularly be performed at least every 6 months until development of dentition is completed.

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.

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).

Paediatric population
Interaction studies have only been performed in adults.

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).

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.

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

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

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 (1 199.32) and INPULSIS-2 (1 199.34)). 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.

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

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. Nintedanib exposure increased dose-proportionally in the dose range of 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).
In an in vitro study, mixing nintedanib capsules with a small amount of apple sauce or chocolate pudding for up to 15 minutes did not have any impact on the pharmaceutical quality. Swelling and deformation of the capsules due to the water uptake of the gelatin capsule shell was observed with

longer exposure time to the soft food. Therefore, taking the capsules with soft food would not be expected to alter the clinical effect when taken immediately.

In a single-dose relative bioavailability study of nintedanib in healthy male adult subjects, administered either as one 100 mg soft gelatin capsule or as four 25 mg soft gelatin capsules, bioavailability was similar in both treatments.

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

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

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

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

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

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

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

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

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

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

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

CTCAE* Adverse reaction
Dose adjustment
Diarrhoea ≥ grade 2 for more than 7 consecutive days despite anti-diarrhoeal treatment OR Diarrhoea ≥ grade 3 despite anti-diarrhoeal treatment After treatment interruption and recovery to grade 1 or baseline, dose reduction from 200 mg twice daily to 150 mg twice daily and – if a 2nd dose reduction is considered necessary – from 150 mg twice daily to 100 mg twice daily.
Vomiting ≥ grade 2
AND/OR
Nausea ≥ grade 3 despite anti-emetic treatment
Other non-haematological or haematological adverse reaction of ≥ grade 3
* CTCAE: Common Terminology Criteria for Adverse Events

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

AST / ALT and bilirubin elevations
Dose adjustment
Elevation of AST and/or ALT values to > 2.5 × ULN in conjunction with total bilirubin elevation to ≥ 1.5 × ULN OR Elevation of AST and/or ALT values to > 5 × ULN After treatment interruption and recovery of transaminase-values to ≤ 2.5 × 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 × ULN in conjunction with an increase of total bilirubin to ≥ 2 × ULN and ALKP < 2 × ULN Unless there is an alternative cause established, Vargatef should be permanently discontinued AST: Aspartate aminotransferase; ALT: Alanine aminotransferase ALKP: Alkaline phosphatase; ULN: Upper limit normal

Special populations

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

Elderly patients (≥ 65 years)
No overall differences in safety and efficacy were observed for elderly patients.
In the pivotal trial 1199.13, 85 patients (12.9% of the patients with adenocarcinoma histology) were ≥ 70 years of age (median age: 72 years, range: 70-80 years) (see section 5.1).
No adjustment of the initial dosing is required in elderly patients (see section 5.2).

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

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

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

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

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

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

Tabulated list of adverse reactions
Table 3 summarizes the frequencies of adverse drug reactions that were reported in the pivotal trial LUME-Lung 1 for patients with NSCLC of adenocarcinoma tumour histology (n = 320) or from the post-marketing period. The following terms are used to rank the ADRs by frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data).
Within each frequency grouping adverse reactions are presented in order of decreased seriousness.

Table 3:
Summary of ADRs per frequency category

System Organ
Class
Very common
(≥ 1/10)
Common
(≥ 1/100 < 1/10)
Uncommon
(≥ 1/1 000
< 1/100)
Not known
Infections and infestations

Febrile neutropenia,
Abscesses,
Sepsis

Blood and lymphatic system disorders
Neutropenia
(includes febrile neutropenia)
Thrombocytopenia

Metabolism and nutrition disorders
Decreased appetite,
Electrolyte imbalance
Dehydration,
Weight decreased

Nervous system disorders
Peripheral neuropathy
Headache1)

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-glutamyltran sferase (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 national reporting system listed in Appendix V.

Gastrointestinal disorders
Diarrhoea was the most frequently reported gastro-intestinal adverse reaction and appeared in close temporal relationship with the administration of docetaxel (see section 4.8). In the clinical trial LUME-Lung 1 (see section 5.1), the majority of patients had mild to moderate diarrhoea.
Serious cases of diarrhoea leading to dehydration and electrolyte disturbances have been reported with nintedanib in the post-marketing period. Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, for example loperamide, and may require interruption, dose reduction or discontinuation of therapy with Vargatef (see section 4.2).

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

In the event of dehydration, administration of electrolytes and fluids is required. Plasma levels of

electrolytes should be monitored, if relevant gastrointestinal adverse events occur. Interruption, dose reduction or discontinuation of therapy with Vargatef may be required (see section 4.2).

Neutropenia and sepsis
A higher frequency of neutropenia of CTCAE grade ≥ 3 was observed in patients treated with Vargatef in combination with docetaxel as compared to treatment with docetaxel alone.
Subsequent complications such as sepsis or febrile neutropenia have been observed (including fatal cases).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Gastrointestinal perforations 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 Vargatef 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. Vargatef should therefore only be initiated at least 4 weeks after major surgery. Therapy with Vargatef should be permanently discontinued in patients who develop gastrointestinal perforation. In patients who develop ischaemic colitis Vargatef should be discontinued, and exceptionally, Vargatef 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 Vargatef 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 Vargatef should therefore only be initiated or – in case of perioperative interruption – resumed based on clinical judgement of adequate wound healing.

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

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

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

Interaction studies have only been performed in adults.

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

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

Cytochrome (CYP)-enzymes
Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways. Nintedanib and its metabolites, the free acid moiety BIBF 1202 and its glucuronide BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in preclinical studies (see section 5.2). The likelihood of drug-drug interactions with nintedanib based on CYP metabolism is therefore considered to be low.

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

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).

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 Vargatef and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of Vargatef. 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 Vargatef in pregnant women, but preclinical studies in animals have shown reproductive toxicity of this active substance (see section 5.3). As nintedanib may cause foetal harm also in humans, it should not be used during pregnancy unless the clinical condition requires treatment. Pregnancy testing should be conducted at least prior to treatment with Vargatef.
Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy with Vargatef.

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

Breast-feeding
There is no information on the excretion of nintedanib and its metabolites in human milk.
Preclinical studies showed that small amounts of nintedanib and its metabolites (≤ 0.5% of the

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

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

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

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

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action
Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and ß) and fibroblast growth factor receptors (FGFR 1-3) kinase activity. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling which is crucial for the proliferation and survival of endothelial as well as perivascular cells (pericytes and vascular smooth muscle cells). In addition Fms-like tyrosine-protein kinase (Flt)-3, lymphocyte-specific tyrosine-protein kinase (Lck) and proto-oncogene tyrosine-protein kinase Src (Src) are inhibited.

Pharmacodynamic effects
Tumour angiogenesis is an essential feature contributing to tumour growth, progression and metastasis formation and is predominantly triggered by the release of pro-angiogenic factors secreted by the tumour cell (i.e. VEGF and bFGF) to attract host endothelial as well as perivascular cells to facilitate oxygen and nutrient supply through the host vascular system. In preclinical disease models nintedanib, as single agent, effectively interfered with the formation and maintenance of the tumour vascular system resulting in tumour growth inhibition and tumour stasis. In particular, treatment of tumour xenografts with nintedanib led to a rapid reduction in tumour micro vessel density, pericytes vessel coverage and tumour perfusion.

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

Clinical efficacy and safety
Efficacy in the pivotal phase 3 trial LUME-Lung 1
The efficacy and safety of Vargatef was investigated in 1 314 adult patients with locally advanced, metastatic or recurrent NSCLC after one prior line of chemotherapy. ‘Locally recurrent’ was defined as local re-occurrence of the tumour without metastases at trial entry. The trial included 658 patients (50.1%) with adenocarcinoma, 555 patients (42.2%) with squamous cell carcinoma, and 101 patients (7.7%) with other tumour histologies.

Absorption
Nintedanib reached maximum plasma concentrations approximately 2-4 hours after oral administration as soft gelatin capsule under fed conditions (range 0.5-8 hours). The absolute bioavailability of a 100 mg dose was 4.69% (90% CI: 3.615-6.078) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.
Nintedanib exposure increased dose-proportionally in the dose range of 50-450 mg once daily and 150-300 mg twice daily. Steady state plasma concentrations were achieved within one week of dosing at the latest.

After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (CI: 95.3-152.5%) and absorption was delayed (median tmax fasted: 2.00 hours;
fed: 3.98 h).
In an in vitro study, mixing nintedanib capsules with a small amount of apple sauce or chocolate pudding for up to 15 minutes did not have any impact on the pharmaceutical quality. Swelling and deformation of the capsules due to the water uptake of the gelatin capsule shell was observed with longer exposure time to the soft food. Therefore, taking the capsules with soft food would not be expected to alter the clinical effect when taken immediately.

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 UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide.