OFEV 100mg capsule me medication leaflet

Ofev 25 mg soft capsules

Ofev 100 mg soft capsules

Ofev 150 mg soft capsules

Ofev 25 mg soft capsules

One soft capsule contains 25 mg nintedanib (as esilate)

Each 25 mg soft capsule contains 0.3 mg of soya lecithin.

Ofev 100 mg soft capsules

One soft capsule contains 100 mg nintedanib (as esilate)

Each 100 mg soft capsule contains 1.2 mg of soya lecithin.

Ofev 150 mg soft capsules

One soft capsule contains 150 mg nintedanib (as esilate)

Each 150 mg soft capsule contains 1.8 mg of soya lecithin.

For the full list of excipients, see section 6.1.

Soft capsule (capsule).

Ofev 25 mg soft capsules

Ofev 25 mg soft capsules are orange-coloured, opaque, oval soft-gelatin capsules (approx. 8 x 5 mm)imprinted on one side in black with “25”.

Ofev 100 mg soft capsules

Ofev 100 mg soft capsules are peach-coloured, opaque, oblong soft-gelatin capsules(approx. 16 x 6 mm) marked on one side with the Boehringer Ingelheim company symbol and “100”.

Ofev 150 mg soft capsules

Ofev 150 mg soft capsules are brown-coloured, opaque, oblong soft-gelatin capsules(approx. 18 x 7 mm) marked on one side with the Boehringer Ingelheim company symbol and “150”.

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 clinicallysignificant, 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 ofsystemic sclerosis associated interstitial lung disease (SSc-ILD).

Adults: Treatment should be initiated by physicians experienced in the management of diseases forwhich 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 fibrosinginterstitial lung diseases (ILDs).

* 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 the150 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 dailydose of 300 mg should not be exceeded.

In addition to symptomatic treatment if applicable, the management of adverse reactions to Ofev (seesections 4.4 and 4.8) could include dose reduction and temporary interruption until the specificadverse reaction has resolved to levels that allow continuation of therapy. Ofev treatment may beresumed at the full dose (150 mg twice daily in adult patients) or a reduced dose (100 mg twice dailyin adult patients). If an adult patient does not tolerate 100 mg twice daily, treatment with Ofev shouldbe discontinued.

If diarrhoea, nausea and/or vomiting persist despite appropriate supportive care (including anti-emetictherapy), dose reduction or treatment interruption may be required. The treatment may be resumed at areduced dose (100 mg twice daily in adult patients) or at the full dose (150 mg twice daily in adultpatients). In case of persisting severe diarrhoea, nausea and/or vomiting despite symptomatictreatment, 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 paediatricpopulation, 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 annualbone imaging is recommended in patients with open epiphyses. Treatment interruption should beconsidered 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 ofdentition 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 thepatient’s weight and is administered twice daily, approximately 12 hours apart (see Table 1). The doseshould be adjusted according to weight as treatment progresses.

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

Weight range Ofev dose Ofev reduced dose*13.5** - 22.9 kg 50 mg (two 25 mg capsules) 25 mg (one 25 mg capsule)twice daily twice daily23.0 - 33.4 kg 75 mg (three 25 mg capsules) 50 mg (two 25 mg capsules)twice daily twice daily33.5 - 57.4 kg 100 mg (one 100 mg capsule or 75 mg (three 25 mg capsules)four 25 mg capsules) twice twice dailydaily57.5 kg and above 150 mg (one 150 mg capsule or 100 mg (one 100 mg capsule orsix 25 mg capsules) twice daily four 25 mg capsules) twicedaily

*Reduced dose is recommended in children and adolescents with mild hepatic impairment (Child

Pugh A) and for the management of adverse reactions in the paediatric population. For moreinformation on the management of adverse drug reactions, see above.

**Weight below 13.5 kg:

Treatment should be interrupted in case the patient experiences a weight decrease below 13.5 kg.

Elderly patients (≥ 65 years)

No overall differences in safety and efficacy were observed for elderly patients. No a-priori doseadjustment is required in elderly patients. Patients ≥ 75 years may be more likely to require dosereduction to manage adverse effects (see section 5.2).

Adjustment of the starting dose in adult and paediatric patients with mild to moderate renalimpairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not beenstudied in adult and paediatric patients with severe renal impairment (< 30 mL/min creatinineclearance).

In adult patients with mild hepatic impairment (Child Pugh A), the recommended dose of Ofev is100 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 patientswith mild hepatic impairment (Child Pugh A), treatment interruption or discontinuation formanagement of adverse reactions should be considered.

The safety and efficacy of nintedanib have not been investigated in adult and paediatric patients withhepatic impairment classified as Child Pugh B and C. Treatment of adult and paediatric patients withmoderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Ofev is notrecommended (see section 5.2).

The safety and efficacy of nintedanib have not been studied in paediatric patients below 6 years old.

Therefore, treatment of children below 6 years old with nintedanib is not recommended. Nintedanibhas not been studied in patients with a weight below 13.5 kg and therefore, it is not recommended inthis population (see section 5.1).

Ofev is for oral use. The capsules should be taken with food, swallowed whole with water, and shouldnot be chewed. The capsule should not be opened or crushed (see section 6.6). Ofev capsules may betaken with a small amount (one teaspoonful) of cold or room temperature soft food, such as applesauce or chocolate pudding, and must be swallowed unchewed immediately, to ensure the capsulestays intact.

* Pregnancy (see section 4.6)

* Hypersensitivity to nintedanib, to peanut or soya, or to any of the excipients listed insection 6.1.

In the clinical trials, diarrhoea was the most frequent gastro-intestinal adverse reaction reported (seesection 4.8). In most patients, the adverse reaction was of mild to moderate intensity and occurredwithin the first 3 months of treatment.

Serious cases of diarrhoea leading to dehydration and electrolyte disturbances have been reported inthe post-marketing. Patients should be treated at first signs with adequate hydration and anti-diarrhoealmedicinal products, e.g. loperamide, and may require dose reduction or treatment interruption. Ofevtreatment may be resumed at a reduced dose or at the full dose (see section 4.2). In case of persistingsevere 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). Inmost 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 reductionor treatment interruption may be required. The treatment may be resumed at a reduced dose or at thefull dose (see section 4.2 Dose adjustments). In case of persisting severe symptoms therapy with Ofevshould be discontinued.

Hepatic function

The safety and efficacy of Ofev has not been studied in patients with moderate (Child Pugh B) orsevere (Child Pugh C) hepatic impairment. Therefore, treatment with Ofev is not recommended insuch patients (see section 4.2). Based on increased exposure, the risk for adverse reactions may beincreased in patients with mild hepatic impairment (Child Pugh A). Adult patients with mild hepaticimpairment (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 severeliver injury with fatal outcome. The majority of hepatic events occur within the first three months oftreatment. Therefore, hepatic transaminase and bilirubin levels should be investigated before treatmentinitiation and during the first month of treatment with Ofev. Patients should then be monitored atregular intervals during the subsequent two months of treatment and periodically thereafter, e.g. ateach 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 inthe majority of cases. If transaminase (AST or ALT) elevations > 3× ULN are measured, dosereduction or interruption of the therapy with Ofev is recommended and the patient should bemonitored closely. Once transaminases have returned to baseline values, treatment with Ofev may beresumed at the full dose or reintroduced at a reduced dose which subsequently may be increased to thefull dose (see section 4.2 Dose adjustments). If any liver test elevations are associated with clinicalsigns or symptoms of liver injury, e.g. jaundice, treatment with Ofev should be permanentlydiscontinued. 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 ofelevations of liver enzymes. Nintedanib exposure increased linearly with patient age, which may alsoresult in a higher risk of developing liver enzyme elevations (see section 5.2). Close monitoring isrecommended in patients with these risk factors.

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

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

Vascular endothelial growth factor receptor (VEGFR) inhibition might be associated with an increasedrisk of bleeding.

Patients at known risk for bleeding including patients with inherited predisposition to bleeding orpatients 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 productsthat could cause bleeding). Therefore, these patients should only be treated with Ofev if the anticipatedbenefit outweighs the potential risk.

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 (Ofev2.5% 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 patientsexperienced 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 placebogroups. 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 inthe placebo group (0.7%) and not observed in the Ofev group.

Caution should be used when treating patients at higher cardiovascular risk including known coronaryartery disease. Treatment interruption should be considered in patients who develop signs orsymptoms of acute myocardial ischemia.

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

In the clinical trials, no increased risk of venous thromboembolism was observed in nintedanib treatedpatients. Due to the mechanism of action of nintedanib patients might have an increased risk ofthromboembolic 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 bothtreatment groups. Due to the mechanism of action of nintedanib, patients might have an increased riskof 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 shouldbe exercised when treating patients with previous abdominal surgery, previous history of pepticulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs. Ofev should onlybe initiated at least 4 weeks after abdominal surgery. Therapy with Ofev should be permanentlydiscontinued in patients who develop gastrointestinal perforation or ischaemic colitis. Exceptionally,

Ofev can be reintroduced after complete resolution of ischaemic colitis and careful assessment ofpatient’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 beenreported post-marketing. Histological findings in individual cases were consistent with glomerularmicroangiopathy 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 beconsidered in patients who develop signs or symptoms of nephrotic syndrome.

VEGF pathway inhibitors have been associated with thrombotic microangiopathy (TMA), includingvery few case reports for nintedanib. If laboratory or clinical findings associated with TMA occur in apatient receiving nintedanib, treatment with nintedanib should be discontinued and thoroughevaluation 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 withheadache, hypertension, visual disturbances, seizure, lethargy, confusion and other visual andneurologic disturbances, and can be fatal. PRES has been reported with other VEGF inhibitors.

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

Administration of Ofev may increase blood pressure. Systemic blood pressure should be measuredperiodically and as clinically indicated.

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 parenteralepoprostenol/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 isrecommended 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 themechanism of action nintedanib may impair wound healing. No dedicated studies investigating theeffect of nintedanib on wound healing were performed. Treatment with Ofev should therefore only beinitiated or - in case of perioperative interruption - resumed based on clinical judgement of adequatewound healing.

Co-administration with pirfenidone

In a dedicated pharmacokinetic study, concomitant treatment of nintedanib with pirfenidone wasinvestigated in patients with IPF. Based on these results, there is no evidence of a relevantpharmacokinetic drug-drug interaction between nintedanib and pirfenidone when administered incombination (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.

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, cautionshould 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 personswith soya allergy (see section 4.3). Patients with known allergy to peanut protein carry an enhancedrisk for severe reactions to soya preparations.

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

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

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). Inthe paediatric clinical trial, significant reductions in growth rate were not observed while receivingnintedanib. However, long term safety data in paediatric patients are not available.

Growth must be regularly monitored, and evaluation of epiphyseal growth plate alteration via annualbone imaging is recommended in patients with open epiphyses. Treatment interruption should beconsidered in patients who develop signs of growth impairment or epiphyseal growth platesalterations.

Tooth development disorders

Tooth development disorders were observed in preclinical studies (see section 5.3). In the paediatricclinical trial, the risk of tooth development disorders was not confirmed.

As a precautionary measure, oral dental examination must regularly be performed at least every6 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 inhibitorketoconazole increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on Cmax ina dedicated drug-drug interaction study. In a drug-drug interaction study with the potent P-gp inducerrifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on Cmaxupon co-administration with rifampicin compared to administration of nintedanib alone. If co-administered with Ofev, potent P-gp inhibitors (e.g. ketoconazole, erythromycin or cyclosporine) mayincrease exposure to nintedanib. In such cases, patients should be monitored closely for tolerability ofnintedanib. Management of adverse reactions may require interruption, dose reduction, ordiscontinuation of therapy with Ofev (see section 4.2).

Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decreaseexposure 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. Nintedaniband its metabolites, the free acid moiety BIBF 1202 and its glucuronide BIBF 1202 glucuronide, didnot inhibit or induce CYP enzymes in preclinical studies (see section 5.2). The likelihood of drug-druginteractions with nintedanib based on CYP metabolism is therefore considered to be low.

Co-administration with other medicinal products

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

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

Interaction studies have only been performed in adults.

Nintedanib may cause foetal harm in humans (see section 5.3). Women of childbearing potentialshould be advised to avoid becoming pregnant while receiving treatment with Ofev and to use highlyeffective 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 vomitingand/or diarrhoea or other conditions where the absorption may be affected. Women taking oralhormonal contraceptives experiencing these conditions should be advised to use an alternative highlyeffective contraceptive measure.

There is no information on the use of Ofev in pregnant women, but pre-clinical studies in animals haveshown reproductive toxicity of this active substance (see section 5.3). As nintedanib may cause foetalharm also in humans, it must not be used during pregnancy (see section 4.3) and pregnancy testingmust 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 duringtherapy with Ofev.

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

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 theadministered dose) were secreted into milk of lactating rats. A risk to the newborns/infants cannot beexcluded. Breast-feeding should be discontinued during treatment with Ofev.

Based on preclinical investigations there is no evidence for impairment of male fertility (seesection 5.3). From subchronic and chronic toxicity studies, there is no evidence that female fertility inrats is impaired at a systemic exposure level comparable with that at the maximum recommendedhuman 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 becautious when driving or using machines during treatment with Ofev.

In clinical trials and during the post-marketing experience, the most frequently reported adversereactions associated with the use of nintedanib included diarrhoea, nausea and vomiting, abdominalpain, decreased appetite, weight decreased and hepatic enzyme increased.

For the management of selected adverse reactions see section 4.4.

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

Other chronic Systemic sclerosis

System Organ Class Idiopathic pulmonaryfibrosing ILDs with a associated interstitialpreferred term fibrosisprogressive phenotype lung disease

Thrombocytopenia Uncommon Uncommon Uncommon

Weight decreased Common Common Common

Decreased appetite Common Very common Common

Dehydration Uncommon Uncommon Not known

Headache Common Common Common

Posterior reversible Not known Not known Not knownencephalopathysyndrome

Myocardial infarction Uncommon Uncommon Not known

Bleeding (see Common Common Commonsection 4.4)

Hypertension Uncommon Common Common

Aneurysms and artery Not known Not known Not knowndissections

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

Drug induced liver Uncommon Common Uncommoninjury

Hepatic enzyme Very common Very common Very commonincreased

Frequency

Other chronic Systemic sclerosis

System Organ Class Idiopathic pulmonaryfibrosing ILDs with a associated interstitialpreferred term fibrosisprogressive phenotype lung disease

Alanine Common Very common Commonaminotransferase(ALT) increased

Aspartate Common Common Commonaminotransferase(AST) increased

Gamma glutamyl Common Common Commontransferase (GGT)increased

Hyperbilirubinaemia Uncommon Uncommon Not known

Blood alkaline Uncommon Common Commonphosphatase (ALKP)increased

Rash Common Common Uncommon

Pruritus Uncommon Uncommon Uncommon

Alopecia Uncommon Uncommon Not known

Renal failure (see Not known Not known Uncommonsection 4.4)

Proteinuria Uncommon Uncommon Not known

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

Diarrhoealeading to Ofev 0% 10.7% 0.9% 16.0% 1.0% 22.2%dose reduction

Diarrhoealeading to Ofev 0.2% 4.4% 0.3% 5.7% 0.3% 6.9%discontinuation

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 elevationswere 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 withclinically manifest liver disease.

For further information about special populations, recommended measures and dosing adjustments incase of diarrhoea and hepatic enzyme increased, refer additionally to sections 4.4 and 4.2,respectively.

In clinical trials, the frequency of patients who experienced bleeding was slightly higher in patientstreated 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 bleedingevents 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 centralnervous 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 comparablebetween the treatment arms (Ofev 0.8% versus placebo 0.5% for INPULSIS; Ofev 1.5% versusplacebo 1.8% for INBUILD; Ofev 1.0% versus placebo 0.0% for SENSCIS). Nephrotic syndrome hasnot been reported in clinical trials. Very few cases of nephrotic range proteinuria with or without renalfunction impairment have been reported post-marketing. Histological findings in individual cases wereconsistent with glomerular microangiopathy with or without renal thrombi. Reversal of the symptomshas been observed after Ofev was discontinued, with residual proteinuria in some cases. Treatmentinterruption should be considered in patients who develop signs or symptoms of nephrotic syndrome(see section 4.4).

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 variableduration (see section 5.1). Consistent with the safety profile seen in adult patients with IPF, otherchronic fibrosing ILDs with progressive phenotype and SSc-ILD, the most frequently reported adversereactions 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 fordrug-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 risksin the paediatric clinical trial (see section 4.2, pct. 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 toweek 52, the percentage of patients with pathological findings was nintedanib/nintedanib: 11.5% andplacebo/nintedanib: 15.4%.

The percentage of patients with treatment-emergent pathological findings on dental examination orimaging, which was 46.2% in the nintedanib group and 38.5% in the placebo group up to week 24. Upto 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 potentialimpact on growth, tooth development, puberty, and the risk of liver injury.

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

There is no specific antidote or treatment for Ofev overdose. Two patients in the oncology programmehad an overdose of maximum 600 mg twice daily up to eight days. Observed adverse reactions wereconsistent with the known safety profile of nintedanib, i.e. increased liver enzymes and gastrointestinalsymptoms. Both patients recovered from these adverse reactions. In the INPULSIS trials, one patientwas inadvertently exposed to a dose of 600 mg daily for a total of 21 days. A non-serious adverseevent (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset ofother reported events. In case of overdose, treatment should be interrupted and general supportivemeasures initiated as appropriate.

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

Nintedanib is a small molecule tyrosine kinase inhibitor including the receptors platelet-derivedgrowth 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 (colonystimulating factor 1 receptor) kinases. Nintedanib binds competitively to the adenosine triphosphate(ATP) binding pocket of these kinases and blocks the intracellular signalling cascades, which havebeen demonstrated to be involved in the pathogenesis of fibrotic tissue remodelling in interstitial lungdiseases.

In in vitro studies using human cells nintedanib has been shown to inhibit processes assumed to beinvolved in the initiation of the fibrotic pathogenesis, the release of pro-fibrotic mediators fromperipheral blood monocytic cells and macrophage polarisation to alternatively activated macrophages.

Nintedanib has been demonstrated to inhibit fundamental processes in organ fibrosis, proliferation andmigration of fibroblasts and transformation to the active myofibroblast phenotype and secretion ofextracellular 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 andanti-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 vascularremodelling by reducing the proliferation of vascular smooth muscle cells, the thickness of pulmonaryvessel walls and percentage of occluded pulmonary vessels.

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 diffusingcapacity (DLCO, corrected for haemoglobin) < 30% predicted at baseline were excluded from thetrials. Patients were randomized in a 3:2 ratio to treatment with Ofev 150 mg or placebo twice dailyfor 52 weeks.

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

Annual rate of decline in FVC

The annual rate of decline of FVC (in mL) was significantly reduced in patients receiving nintedanibcompared to patients receiving placebo. The treatment effect was consistent in both trials. See Table 4for individual and pooled study results.

Table 4: Annual rate of decline in FVC (mL) in trials INPULSIS-1, INPULSIS-2 and theirpooled data - treated set

INPULSIS-1 and

INPULSIS-1 INPULSIS-2 INPULSIS-2 pooled

Placebo Ofev Placebo Ofev Placebo Ofev150 mg 150 mg 150 mgtwice daily twice daily twice daily

Number ofanalysed patients 204 309 219 329 423 638

Rate1 (SE) ofdecline over -239.9 -114.7 -207.3 -113.6 -223.5 -113.652 weeks (18.71) (15.33) (19.31) (15.73) (13.45) (10.98)

Comparison vs placebo

Difference1 125.3 93.7 109.995% CI (77.7, (44.8, (75.9,172.8) 142.7) 144.0)p-value < 0.0001 0.0002 < 0.00011 Estimated based on a random coefficient regression model.

CI: confidence interval

In a sensitivity analysis which assumed that in patients with missing data at week 52 the FVC declineafter the last observed value would be the same as in all placebo patients, the adjusted difference in theannual rate of decline between nintedanib and placebo was 113.9 mL/year (95% CI 69.2, 158.5) in

INPULSIS-1 and 83.3 mL/year (95% CI 37.6, 129.0) in INPULSIS-2.

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

Figure 1: Mean (SEM) observed FVC change from baseline (mL) over time, studies

INPULSIS-1 and INPULSIS-2 pooledbid = twice daily

FVC responder analysis

In both INPULSIS trials, the proportion of FVC responders, defined as patients with an absolutedecline in FVC % predicted no greater than 5% (a threshold indicative of the increasing risk ofmortality in IPF), was significantly higher in the nintedanib group as compared to placebo. Similarresults were observed in analyses using a conservative threshold of 10%. See Table 5 for individualand pooled study results.

Table 5: Proportion of FVC responders at 52 weeks in trials INPULSIS-1, INPULSIS-2 andtheir pooled data - treated set

INPULSIS-1 and

INPULSIS-1 INPULSIS-2 INPULSIS-2 pooled

Placebo Ofev Placebo Ofev Placebo Ofev150 mg 150 mg 150 mgtwice daily twice daily twice daily

Number ofanalysedpatients 204 309 219 329 423 6385% threshold

Number (%) of

FVCresponders1 78 (38.2) 163 (52.8) 86 (39.3) 175 (53.2) 164 (38.8) 338 (53.0)

Comparison vs placebo

Odds ratio 1.85 1.79 1.8495% CI (1.28, 2.66) (1.26, 2.55) (1.43, 2.36)p-value2 0.0010 0.0011 < 0.000110% threshold

Number (%) of

FVC 140responders1 116 (56.9) 218 (70.6) (63.9) 229 (69.6) 256 (60.5) 447 (70.1)

Comparison vs placebo

Odds ratio 1.91 1.29 1.5895% CI (1.32, 2.79) (0.89, 1.86) (1.21, 2.05)p-value2 0.0007 0.1833 0.00071 Responder patients are those with no absolute decline greater than 5% or greater than 10% in

FVC % predicted, depending on the threshold and with an FVC evaluation at 52 weeks.2 Based on a logistic regression.

Time to progression (≥ 10% absolute decline of FVC % predicted or death)

In both INPULSIS trials, the risk of progression was statistically significantly reduced for patientstreated with nintedanib compared with placebo. In the pooled analysis, the HR was 0.60 indicating a40% reduction in the risk of progression for patients treated with nintedanib compared with placebo.

Table 6: Frequency of patients with ≥ 10% absolute decline of FVC % predicted or deathover 52 weeks and time to progression in trials INPULSIS-1, INPULSIS-2, and theirpooled data - treated set

INPULSIS-1 and

INPULSIS-1 INPULSIS-2 INPULSIS-2 pooled

Placebo Ofev Placebo Ofev Placebo Ofev150 mg 150 mg 150 mgtwice daily twice daily twice daily

Number at risk 204 309 219 329 423 638

Patients with 175events, N (%) 83 (40.7) 75 (24.3) 92 (42.0) 98 (29.8) (41.4) 173 (27.1)

Comparison vs placebo1p-value2 0.0001 0.0054 < 0.0001

Hazard ratio3 0.53 0.67 0.6095% CI (0.39, 0.72) (0.51, 0.89) (0.49, 0.74)1 Based on data collected up to 372 days (52 weeks + 7 day margin).2 Based on a Log-rank test.3 Based on a Cox’s regression model.

Change from baseline in SGRQ total score at week 52

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

Time to first acute IPF exacerbation

In the pooled analysis of the INPULSIS trials, a numerically lower risk of first acute exacerbation wasobserved in patients receiving nintedanib compared to placebo. See Table 7 for individual and pooledstudy results.

Table 7: Frequency of patients with acute IPF exacerbations over 52 weeks and time to firstexacerbation analysis based on investigator-reported events in trials INPULSIS-1,

INPULSIS-2, and their pooled data - treated set

INPULSIS-1 and

INPULSIS-1 INPULSIS-2 INPULSIS-2 pooled

Placebo Ofev Placebo Ofev Placebo Ofev150 mg 150 mg 150 mgtwice daily twice daily twice daily

Number at risk 204 309 219 329 423 638

Patients with events,

N (%) 11 (5.4) 19 (6.1) 21 (9.6) 12 (3.6) 32 (7.6) 31 (4.9)

Comparison vs placebo1p-value2 0.6728 0.0050 0.0823

Hazard ratio3 1.15 0.38 0.6495% CI (0.54, 2.42) (0.19, 0.77) (0.39, 1.05)1 Based on data collected up to 372 days (52 weeks + 7 day margin).2 Based on a Log-rank test.3 Based on a Cox’s regression model.

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

Survival analysis

In the pre-specified pooled analysis of survival data of the INPULSIS trials, overall mortality over52 weeks was lower in the nintedanib group (5.5%) compared with the placebo group (7.8%). Theanalysis of time to death resulted in a HR of 0.70 (95% CI 0.43, 1.12; p = 0.1399). The results of allsurvival endpoints (such as on-treatment mortality and respiratory mortality) showed a consistentnumerical difference in favour of nintedanib.

Table 8: All-cause mortality over 52 weeks in trials INPULSIS-1, INPULSIS-2, and theirpooled data - treated set

INPULSIS-1 and

INPULSIS-1 INPULSIS-2 INPULSIS-2 pooled

Placebo Ofev Placebo Ofev Placebo Ofev150 mg 150 mg 150 mg twicetwice daily twice daily daily

Number at risk 204 309 219 329 423 638

Patients with events,

N (%) 13 (6.4) 13 (4.2) 20 (9.1) 22 (6.7) 33 (7.8) 35 (5.5)

Comparison vs placebo1p-value2 0.2880 0.2995 0.1399

Hazard ratio3 0.63 0.74 0.7095% CI (0.29, 1.36) (0.40, 1.35) (0.43, 1.12)1 Based on data collected up to 372 days (52 weeks + 7 day margin).

2 Based on a Log-rank test.3 Based on a Cox’s regression model.

Long-term treatment with Ofev in patients with IPF (INPULSIS-ON)

An open-label extension trial of Ofev included 734 patients with IPF. Patients who completed the52-week treatment period in an INPULSIS trial received open-label Ofev treatment in the extensiontrial INPULSIS-ON. Median exposure time for patients treated with Ofev in both the INPULSIS and

INPULSIS-ON trials was 44.7 months (range 11.9-68.3). The exploratory efficacy endpoints includedthe annual rate of decline in FVC over 192 weeks which was -135.1 (5.8) mL/year in all patientstreated and were consistent with the annual rate of FVC decline in patients treated with Ofev in the

INPULSIS phase III trials (-113.6 mL per year). The adverse event profile of Ofev in INPULSIS-ONwas consistent to that in the INPULSIS phase III trials.

IPF patients with advanced lung function impairment (INSTAGE)

INSTAGE was a multicentre, multinational, prospective, randomised, double-blind, parallel-groupclinical trial in IPF patients with advanced lung function impairment (DLCO ≤ 35% predicted) for24 weeks. 136 patients were treated with Ofev monotherapy. Primary endpoint result showed areduction of St Georges Respiratory Questionnaire (SGRQ) total score by -0.77 units at week W12,based on adjusted mean change from baseline. A post hoc comparison demonstrated that the decline in

FVC in these patients was consistent with the decline in FVC in patients with less advanced diseaseand treated with Ofev in the INPULSIS phase III trials.

The safety and tolerability profile of Ofev in IPF patients with advanced lung function impairment wasconsistent with that seen in the INPULSIS phase III trials.

Additional data from the phase IV INJOURNEY trial with Ofev 150 mg twice daily and add-onpirfenidone

Concomitant treatment with nintedanib and pirfenidone has been investigated in an exploratory open-label, randomised trial of nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mgthree times a day) compared to nintedanib 150 mg twice daily alone in 105 randomised patients for12 weeks. The primary endpoint was the percentage of patients with gastrointestinal adverse eventsfrom baseline to week 12. Gastrointestinal adverse events were frequent and in line with theestablished safety profile of each component. Diarrhoea, nausea and vomiting were the most frequentadverse events reported in patients, treated with pirfenidone added to nintedanib versus nintedanibalone, respectively.

Mean (SE) absolute changes from baseline in FVC at week 12 were -13.3 (17.4) mL in patients treatedwith nintedanib with add-on pirfenidone (n = 48) compared to -40.9 (31.4) mL in patients treated withnintedanib alone (n = 44).

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

The clinical efficacy of Ofev has been studied in patients with other chronic fibrosing ILDs with aprogressive phenotype in a double-blind, randomised, placebo-controlled phase III trial (INBUILD).

Patients with IPF were excluded. Patients with a clinical diagnosis of a chronic fibrosing ILD wereselected if they had relevant fibrosis (greater than 10% fibrotic features) on HRCT and presented withclinical signs of progression (defined as FVC decline ≥ 10%, FVC decline ≥ 5% and < 10% withworsening symptoms or imaging, or worsening symptoms and worsening imaging all in the 24 monthsprior to screening). Patients were required to have an FVC greater than or equal to 45% of predictedand a DLCO 30% to less than 80% of predicted. Patients were required to have progressed despitemanagement deemed appropriate in clinical practice for the patient’s relevant ILD.

A total of 663 patients were randomised in a 1:1 ratio to receive either Ofev 150 mg bid or matchingplacebo for at least 52 weeks. The median Ofev exposure over the whole trial was 17.4 months and themean Ofev exposure over the whole trial was 15.6 months. Randomisation was stratified based on

HRCT fibrotic pattern as assessed by central readers. 412 patients with HRCT with usual interstitialpneumonia (UIP)-like fibrotic pattern and 251 patients with other HRCT fibrotic patterns wererandomised. There were 2 co-primary populations defined for the analyses in this trial: all patients (theoverall population) and patients with HRCT with UIP-like fibrotic pattern. Patients with other HRCTfibrotic patterns represented the ‘complementary’ population.

The primary endpoint was the annual rate of decline in forced vital capacity (FVC) (in mL) over52 weeks. Main secondary endpoints were absolute change from baseline in King’s Brief Interstitial

Lung Disease Questionnaire (K-BILD) total score at week 52, time to first acute ILD exacerbation ordeath over 52 weeks, and time to death over 52 weeks.

Patients had a mean (standard deviation [SD, Min-Max]) age of 65.8 (9.8, 27-87) years and a mean

FVC percent predicted of 69.0% (15.6, 42-137). The underlying clinical ILD diagnoses in groupsrepresented in the trial were hypersensitivity pneumonitis (26.1%), autoimmune ILDs (25.6%),idiopathic nonspecific interstitial pneumonia (18.9%), unclassifiable idiopathic interstitial pneumonia(17.2%), and other ILDs (12.2%).

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

Annual rate of decline in FVC

The annual rate of decline in FVC (in mL) over 52 weeks was significantly reduced by 107.0 mL inpatients receiving Ofev compared to patients receiving placebo (Table 9) corresponding to a relativetreatment effect of 57.0%.

Table 9: Annual rate of decline in FVC (mL) over 52 weeks

Placebo Ofev150 mg twice daily

Number of analysed patients 331 332

Rate1 (SE) of decline over52 weeks -187.8 (14.8) -80.8 (15.1)

Comparison vs placebo

Difference1 107.095% CI (65.4, 148.5)p-value < 0.00011 Based on a random coefficient regression with fixed categorical effects of treatment, HRCT pattern, fixedcontinuous effects of time, baseline FVC [mL], and including treatment-by-time and baseline-by-timeinteractions

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

Figure 2: Forest plot of the annual rate of decline in FVC (mL) over 52 weeks in the patientpopulationsbid = twice daily

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

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

Figure 3: Mean (SEM) observed FVC change from baseline (mL) over 52 weeksbid = twice daily

In addition, favourable effects of Ofev were observed on the adjusted mean absolute change frombaseline in FVC % predicted at week 52. The adjusted mean absolute change from baseline to week 52in FVC % predicted was lower in the nintedanib group (-2.62%) than in the placebo group (-5.86%).

The adjusted mean difference between the treatment groups was 3.24 (95% CI: 2.09, pct. 4.40, nominalp< 0.0001).

FVC responder analysis

The proportion of FVC responders, defined as patients with a relative decline in FVC % predicted nogreater than 5%, was higher in the Ofev group as compared to placebo. Similar results were observedin analyses using a threshold of 10% (Table 10).

Table 10: Proportion of FVC responders at 52 weeks in INBUILD

Placebo Ofev150 mg twice daily

Number of analysed patients 331 3325% threshold

Number (%) of FVCresponders1 104 (31.4) 158 (47.6)

Comparison vs placebo

Odds ratio² 2.0195% CI (1.46, 2.76)

Nominal p-value < 0.000110% threshold

Number (%) of FVCresponders1 169 (51.1) 197 (59.3)

Comparison vs placebo

Odds ratio² 1.4295% CI (1.04, 1.94)

Nominal p-value 0.02681 Responder patients are those with no relative decline greater than 5% or greater than 10% in FVC %predicted, depending on the threshold and with an FVC evaluation at 52 weeks (patients with missing data atweek 52 were considered as non-responders).2 Based on a logistic regression model with continuous covariate baseline FVC % predicted and binarycovariate HRCT pattern

Time to first acute ILD exacerbation or death

Over the whole trial, the proportion of patients with at least one event of first acute ILD exacerbationor death was 13.9% in the Ofev group and 19.6% in the placebo group. The HR was 0.67 (95% CI:

0.46, 0.98; nominal p = 0.0387), indicating a 33% reduction in the risk of first acute ILD exacerbationor death in patients receiving Ofev compared to placebo (Figure 4).

Figure 4: Kaplan-Meier plot of time to first acute ILD exacerbation or death over the wholetrialbid = twice daily

Survival analysis

The risk of death was lower in the Ofev group compared to the placebo group. The HR was 0.78 (95%

CI: 0.50, 1.21; nominal p = 0.2594), indicating a 22% reduction in the risk of death in patientsreceiving Ofev compared to placebo.

Time to progression (≥ 10% absolute decline of FVC % predicted) or death

In the INBUILD trial, the risk of progression (≥ 10% absolute decline of FVC % predicted) or deathwas reduced for patients treated with Ofev. The proportion of patients with an event was 40.4% in the

Ofev group and 54.7% in the placebo group. The HR was 0.66 (95% CI: 0.53, 0.83; p = 0.0003),indicating a 34% reduction of the risk of progression (≥ 10% absolute decline of FVC % predicted)or death in patients receiving Ofev compared to placebo.

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

The adjusted mean absolute change from baseline in Living with Pulmonary Fibrosis (L-PF)symptoms dyspnoea domain score at week 52 was 4.28 in the Ofev group compared with 7.81 in theplacebo group. The adjusted mean difference between the groups in favour of Ofev was -3.53 (95%

CI: -6.14, -0.92; nominal p = 0.0081). The adjusted mean absolute change from baseline in L-PF

Symptoms cough domain score at week 52 was -1.84 in the Ofev group compared with 4.25 in theplacebo group. The adjusted mean difference between the groups in favour of Ofev was -6.09 (95%

CI: -9.65, -2.53; nominal p = 0.0008).

Systemic sclerosis associated interstitial lung disease (SSc-ILD)

The clinical efficacy of Ofev has been studied in patients with SSc-ILD in a double-blind, randomised,placebo-controlled phase III trial (SENSCIS). Patients were diagnosed with SSc-ILD based upon the2013 American College of Rheumatology/European League Against Rheumatism classificationcriteria for SSc and a chest high resolution computed tomography (HRCT) scan conducted within theprevious 12 months. A total of 580 patients were randomised in a 1:1 ratio to receive either Ofev150 mg bid or matching placebo for at least 52 weeks, of which 576 patients were treated.

Randomisation was stratified by antitopoisomerase antibody status (ATA). Individual patients stayedon blinded trial treatment for up to 100 weeks (median Ofev exposure 15.4 months; mean Ofevexposure 14.5 months).

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

In the overall population, 75.2% of the patients were female. The mean (standard deviation [SD, Min-

Max]) age was 54.0 (12.2, 20-79) years. Overall, 51.9% of patients had diffuse cutaneous systemicsclerosis (SSc) and 48.1% had limited cutaneous SSc. The mean (SD) time since first onset of a non-

Raynaud symptom was 3.49 (1.7) years. 49.0% of patients were on stable therapy with mycophenolateat baseline (46.5% mycophenolate mofetil, 1.9% mycophenolate sodium, 0.5% mycophenolic acid).

The safety profile in patients with or without mycophenolate at baseline was comparable.

Annual rate of decline in FVC

The annual rate of decline of FVC (mL) over 52 weeks was significantly reduced by 41.0 mL inpatients receiving Ofev compared to patients receiving placebo (Table 11) corresponding to a relativetreatment effect of 43.8%.

Table 11: Annual rate of decline in FVC (mL) over 52 weeks

Placebo Ofev150 mg twice daily

Number of analysed patients 288 287

Rate1 (SE) of decline over -93.3 (13.5) -52.4 (13.8)52 weeks

Comparison vs placebo

Difference1 41.095% CI (2.9, 79.0)p-value < 0.051 Based on a random coefficient regression with fixed categorical effects of treatment, ATA status, gender,fixed continuous effects of time, baseline FVC [mL], age, height, and including treatment-by-time andbaseline-by-time interactions. Random effect was included for patient specific intercept and time. Within-patient errors were modelled by an unstructured variance-covariance matrix. Inter-individual variability wasmodelled by a variance-components variance-covariance matrix.

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

In addition, similar effects were observed on other lung function endpoints, e.g absolute change frombaseline in FVC in mL at week 52 (Figure 5 and Table 12) and rate of decline in FVC in % predictedover 52 weeks (Table 13) providing further substantiation of the effects of Ofev on slowingprogression of SSc-ILD. Furthermore, fewer patients in the Ofev group had an absolute FVC decline> 5% predicted (20.6% in the Ofev group vs. 28.5% in the placebo group, OR = 0.65, p = 0.0287). Therelative FVC decline in mL > 10% was comparable between both groups (16.7% in the Ofev group vs.

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

An exploratory analysis of data up to 100 weeks (maximum treatment duration in SENSCIS)suggested that the on treatment effect of Ofev on slowing progression of SSc-ILD persisted beyond52 weeks.

Figure 5: Mean (SEM) observed FVC change from baseline (mL) over 52 weeksbid = twice daily

Table 12: Absolute change from baseline in FVC (mL) at week 52

Placebo Ofev150 mg twice daily

Number of analysed patients 288 288

Mean (SD) at Baseline 2 541.0 (815.5) 2 458.5 (735.9)

Mean1 (SE) change from -101.0 (13.6) -54.6 (13.9)baseline at week 52

Comparison vs placebo

Mean1 46.495% CI (8.1, 84.7)p-value < 0.051 Based on Mixed Model for Repeated Measures (MMRM), with fixed categorical effects of ATA status, visit,treatment-by-visit interaction, baseline-by-visit interaction age, gender and height. Visit was the repeatedmeasure. Within-patient errors were modelled by unstructured variance-covariance structure. Adjusted meanwas based on all analysed patients in the model (not only patients with a baseline and measurement atweek 52).

Table 13: Annual rate of decline in FVC (% predicted) over 52 weeks

Placebo Ofev150 mg twice daily

Number of analysed patients 288 287

Rate1 (SE) of decline over -2.6 (0.4) -1.4 (0.4)52 weeks

Comparison vs placebo

Difference1 1.1595% CI (0.09, 2.21)p-value < 0.051 Based on a random coefficient regression with fixed categorical effects of treatment, ATA status, fixedcontinuous effects of time, baseline FVC [% pred], and including treatment-by-time and baseline-by-timeinteractions. Random effect was included for patient specific intercept and time. Within-patient errors weremodelled by an unstructured variance-covariance matrix. Inter-individual variability was modelled by avariance-components variance-covariance matrix

Change from baseline in Modified Rodnan Skin Score (mRSS) at week 52

The adjusted mean absolute change from baseline in mRSS at week 52 was comparable between the

Ofev group (-2.17 (95% CI -2.69, -1.65)) and the placebo group (-1.96 (95% CI -2.48, -1.45)). Theadjusted mean difference between the treatment groups was -0.21 (95% CI -0.94, 0.53; p = 0.5785).

Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score at week 52

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

Survival analysis

Mortality over the whole trial was comparable between the Ofev group (N = 10; 3.5%) and theplacebo group (N = 9; 3.1%). The analysis of time to death over the whole trial resulted in a HR of1.16 (95% CI 0.47, 2.84; p = 0.7535).

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

Clinically significant, progressive fibrosing interstitial lung diseases (ILDs) and systemic sclerosisassociated interstitial lung disease (SSc-ILD) in children and adolescents from 6 to 17 years old

The clinical safety and efficacy of Ofev in children and adolescents from 6 to 17 years with clinicallysignificant fibrosing interstitial lung diseases (ILDs) has been studied in an exploratory randomised,double-blind, placebo-controlled phase III trial (InPedILD 1199.337).

Patients were randomised in a 2:1 ratio to receive either Ofev twice daily (doses adjusted for weight,including the use of a 25 mg capsule) or matching placebo for 24 weeks, followed by open labeltreatment with nintedanib of variable duration. The use of standard of care as deemed clinicallyindicated by the treating physician was allowed.

The primary objectives of the InPedILD trial were to evaluate the dose-exposure and safety ofnintedanib in children and adolescents with clinically significant fibrosing ILD. Efficacy wasevaluated as a secondary objective only.

The InPedILD trial enrolled children and adolescents aged 6 to 17 years with clinically significantfibrosing ILD and FVC of at least 25% predicted. Patients were classified as having fibrosing ILDbased on evidence of fibrosis on two HRCT scans (with one HRCT scan conducted within theprevious 12 months) or evidence of fibrosis on lung biopsy and one HRCT scan conducted within theprevious 12 months.

Clinically significant disease was defined as a Fan score ≥3 or documented evidence of clinicalprogression over any time frame. Evidence of clinical progression was based on a relative decline in

FVC ≥10% predicted, a relative decline in FVC of 5-10% predicted with worsening symptoms,worsening fibrosis on HRCT or other measures of clinical worsening attributed to progressivepulmonary fibrosis (e.g. increased oxygen requirement, decreased diffusion capacity) although thiswas not a requirement for enrolment for patients with a Fan score of ≥3.

In total, 39 patients were randomised (61.5% female). Baseline characteristics:

* 6-11 years: 12 patients, 12-17 years: 27 patients. The mean [standard deviation (SD)] age was12.6 (3.3) years.

* Mean (SD) weight was 42.2 kg (17.8 kg); 6-11 years: 26.6 kg (10.4 kg), 12-17 years: 49.1 kg(16.0 kg).

* The overall baseline mean BMI-for-age-Z-score (SD) was −0.6 (1.8).

* The overall mean FVC Z-score (SD) at baseline was -3.5 (1.9).

The most frequent single underlying ILD diagnoses of enrolled patients were:

* ‘Surfactant protein deficiency’ (nintedanib: 26.9%, placebo: 38.5%),

* ‘Systemic sclerosis’ (nintedanib: 15.4%, placebo: 23.1%),

* ‘Toxic/radiation/drug-induced pneumonitis’ (nintedanib: 11.5%, placebo 7.7%).

* ‘Chronic hypersensitivity pneumonitis’ was reported for 2 patients (nintedanib: 7.7%).

* The remaining underlying ILD diagnoses reported for 1 patient each were:

o Post-HSCT fibrosis,o Juvenile RA,o Juvenile idiopathic arthritis,o Dermatomyositis (DM),o Desquammative Interstitial Pneumonitis,o Influenza H1N1,o Unclear (Chronic Diffuse Pulmonary Lung Disease),o Copa Syndrome,o Copa Gene Mutation,o Undifferentiated Connective Tissue Disease,o Post-Infectious Bronchiolitis Obliterans,o Unspecified ILD,o Idiopathico Sting-associated Vasculopathy.

The primary endpoint results were:

* Exposure to Nintedanib:

o The exposure to nintedanib described as AUCτ,ss based on sampling at steady state wasbroadly similar in children and adolescents and comparable to the AUCτ,ss observed inadults (see section 5.2).

* Treatment-Emergent Adverse Events (Week 24):

o Nintedanib group: 84.6% of patients (6-11 years: 75.0%, 12-17 years: 88.9%)o Placebo group: 84.6% of patients (6-11 years: 100%, 12-17 years: 77.8%)

Change from baseline in Forced Vital Capacity FVC % predicted was investigated as a secondaryefficacy endpoint. Results (Figure 6):

* Week 24:

o Nintedanib group: Adjusted mean change = 0.31 (95% CI: -2.36, 2.98)o Placebo group: Adjusted mean change = -0.89 (95% CI: -4.61, 2.82)o Difference in FVC % predicted 1.21 (95% CI: -3.40, 5.81) in favour of nintedanib.

* Week 52:

o Randomised Nintedanib group: Adjusted mean change = 0.79 (95% CI: -2.95, 4.53)o Randomised Placebo group: Adjusted mean change = -0.98 (95% CI: -6.26, pct. 4.30)

For the FVC % predicted endpoint and a number of other exploratory efficacy endpoints, highvariability in response to treatment with nintedanib was observed amongst paediatric patients.

Figure 6: Adjusted mean (SE) of absolute change from baseline in FVC % predicted over52 weeks - treated set*

* After 24 weeks of treatment, all patients received nintedanib in the open-label part of the trial.

The European Medicines Agency has waived the obligation to submit the results of studies with Ofevin all subsets of the paediatric population in IPF.

The European Medicines Agency has waived the obligation to submit the results of studies with Ofevin paediatric population below 6 years of age in fibrosing ILDs (see section 4.2 for information onpaediatric use).

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

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

3.98 h).

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

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.

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

The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%.

Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributedin plasma with a blood to plasma ratio of 0.869.

The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the freeacid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by uridine 5’-diphospho-glucuronosyltransferase enzymes (UGT) enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and

UGT 1A10 to BIBF 1202 glucuronide.

Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with

CYP 3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not bedetected in plasma in the human ADME study. In vitro, CYP-dependent metabolism accounted forabout 5% compared to about 25% ester cleavage. Nintedanib, BIBF 1202, and BIBF 1202 glucuronidedid not inhibit or induce CYP enzymes in preclinical studies, either. Drug-drug interactions betweennintedanib and CYP substrates, CYP inhibitors, or CYP inducers are therefore not expected.

Total plasma clearance after intravenous infusion was high (CL: 1 390 mL/min, 28.8% gCV). Urinaryexcretion of the unchanged active substance within 48 h was about 0.05% of the dose (31.5% gCV)after oral and about 1.4% of the dose (24.2% gCV) after intravenous administration; the renalclearance was 20 mL/min (32.6% gCV). The major route of elimination of drug related radioactivityafter oral administration of [14C] nintedanib was via faecal/biliary excretion (93.4% of dose,2.61% gCV). The contribution of renal excretion to the total clearance was low (0.649% of dose,26.3% gCV). The overall recovery was considered complete (above 90%) within 4 days after dosing.

The terminal half-life of nintedanib was between 10 and 15 h (gCV % approximately 50%).

The pharmacokinetics (PK) of nintedanib can be considered linear with respect to time (i.e. single-dose data can be extrapolated to multiple-dose data). Accumulation upon multiple administrations was1.04-fold for Cmax and 1.38-fold for AUCτ. Nintedanib trough concentrations remained stable for morethan one year.

Transport

Nintedanib is a substrate of P-gp. For the interaction potential of nintedanib with this transporter, seesection 4.5. Nintedanib was shown to be not a substrate or inhibitor of OATP-1B1, OATP-1B3,

OATP-2B1, OCT-2, or MRP-2 in vitro. Nintedanib was also not a substrate of BCRP. Only a weakinhibitory potential on OCT-1, BCRP, and P-gp was observed in vitro which is considered to be oflow clinical relevance. The same applies for nintedanib being a substrate of OCT-1.

Population pharmocokinetic analysis in special populations

The PK properties of nintedanib were similar in healthy volunteers, patients with IPF, patients withother chronic fibrosing ILDs with a progressive phenotype, patients with SSc-ILD, and cancerpatients. Based on results of a population PK (PopPK) analysis in patients with IPF and non small celllung cancer (NSCLC) (N = 1 191) and descriptive investigations, exposure to nintedanib was notinfluenced by sex (body weight corrected), mild and moderate renal impairment (estimated bycreatinine clearance), alcohol consumption, or P-gp genotype.

PopPK analyses indicated moderate effects on exposure to nintedanib depending on age, body weight,and race (see below). Based on the high inter-individual variability of exposure observed moderateeffects are considered not clinically relevant (see section 4.4).

Exposure to nintedanib increased linearly with age. AUCτ,ss decreased by 16% for a 45-year old patientand increased by 13% for a 76-year old patient relative to a patient with the median age of 62 years.

The age range covered by the analysis was 29 to 85 years; approximately 5% of the population wereolder than 75 years. Based on a PopPK model, an increase in nintedanib exposure of approximately20-25% was observed in patients ≥ 75 years compared with patients under 65 years.

Based on the analysis of pharmacokinetic data of study InPedILD (1199.337), oral administration ofnintedanib according to the weight-based dosing algorithm resulted in exposure within the rangeobserved in adult patients. The observed geometric mean AUCτ,ss (geometric coefficient of variation)exposures were 175 ng/mL·hr (85.1%) and 167 ng/mL·hr (83.6 %) in 10 patients aged 6 to 11 yearsold and 23 patients aged 12 to 17 years old, respectively.

Exposure-response analyses of the data of study InPedILD indicated an Emax-like relationshipbetween exposure and FVC % predicted as well FVC Z-score, supported by adult data. For FVC %predicted, the EC50 was 4.4 ng/mL (relative standard error: 28.6%), while for FVC Z-score, the EC50was 5.0 ng/mL (relative standard error: 75.3%).

Nintedanib was not studied in children and adolescents with hepatic impairment.

In children and adolescents with fibrosing ILD and mild hepatic impairment (Child Pugh class A),population pharmacokinetic modelling indicates that the recommended dose reductions (seesection 4.2) would result in exposures consistent with nintedanib exposures in adult patients with mildhepatic impairment (Child Pugh class A) at the respective recommended reduced dose.

An inverse correlation between body weight and exposure to nintedanib was observed. AUCτ,ssincreased by 25% for a 50 kg patient (5th percentile) and decreased by 19% for a 100 kg patient(95th percentile) relative to a patient with the median weight of 71.5 kg.

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

Caucasians (body weight corrected). Data from Black individuals were very limited but in the samerange as for Caucasians.

In a dedicated single dose phase I study and compared to healthy subjects, exposure to nintedanibbased on Cmax and AUC was 2.2-fold higher in volunteers with mild hepatic impairment(Child Pugh A; 90% CI 1.3-3.7 for Cmax and 1.2-3.8 for AUC, respectively). In volunteers withmoderate hepatic impairment (Child Pugh B), exposure was 7.6-fold higher based on Cmax (90% CI4.4-13.2) and 8.7-fold higher (90% CI 5.7-13.1) based on AUC, respectively, compared to healthyvolunteers. Subjects with severe hepatic impairment (Child Pugh C) have not been studied.

Concomitant treatment with pirfenidone

In a dedicated pharmacokinetic study, concomitant treatment of nintedanib with pirfenidone wasinvestigated in patients with IPF. Group 1 received a single dose of 150 mg nintedanib before and afteruptitration to 801 mg pirfenidone three times a day at steady state (N = 20 patients treated). Group 2received steady state treatment of 801 mg pirfenidone three times a day and had a PK profiling beforeand after at least 7 days of co-treatment with 150 mg nintedanib twice daily (N = 17 patients treated).

In group 1, the adjusted geometric mean ratios (90% confidence interval (CI)) were 93% (57% -151%) and 96% (70% - 131%) for Cmax and AUC0-tz of nintedanib, respectively (n = 12 forintraindividual comparison). In group 2, the adjusted geometric mean ratios (90% CI)) were 97%(86% - 110%) and 95% (86% - 106%) for Cmax,ss and AUCτ,ss of pirfenidone, respectively (n = 12 forintraindividual comparison).

Based on these results, there is no evidence of a relevant pharmacokinetic drug-drug interactionbetween nintedanib and pirfenidone when administered in combination (see section 4.4).

Concomitant treatment with bosentan

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

Concomitant treatment with oral hormonal contraceptives

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

Exposure-response relationship

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

For exposure-response analyses in paediatric population, see sub-section paediatric population.

General toxicology

Single dose toxicity studies in rats and mice indicated a low acute toxic potential of nintedanib. Inrepeat dose toxicology studies in young rats, irreversible changes of enamel and dentin were observedin the continuously fast-growing incisors, but not in premolars or molars. In addition, thickening ofepiphyseal growth plates during bone growth phases was observed and was reversible afterdiscontinuation. These changes are known from other VEGFR-2 inhibitors and can be considered classeffects.

Diarrhoea and vomiting accompanied by reduced food consumption and loss of body weight wereobserved in toxicity studies in non-rodents.

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

Reproduction toxicity

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

In rabbits, embryo-foetal lethality and teratogenic effects were observed at an exposure approximately3 times higher than at the MRHD but equivocal effects on the embryo-foetal development of the axialskeleton and the heart were noted already at an exposure below that at the MRHD of 150 mg twicedaily.

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

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

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

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

Genotoxicity studies indicated no mutagenic potential for nintedanib.

Capsule contenttriglycerides, medium-chainhard fatlecithin (soya) (E322)

Capsule shellgelatinglycerol (85%)titanium dioxide (E171)iron oxide red (E172)iron oxide yellow (E172)

Printing ink (applicable only to Ofev 25 mg soft capsules)shellaciron oxide black (E172)propylene glycol (E1520)

Not applicable.

Ofev 25 mg soft capsules4 years

Ofev 100 and 150 mg soft capsules3 years

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

Do not store above 25 °C. Keep the bottle tightly closed in order to protect from moisture.

Ofev 25 mg soft capsules

Ofev 25 mg soft capsules are available in the following pack-sizes:

- 60 × 1 soft capsules in aluminium/aluminium perforated unit dose blisters

- 60 soft capsules in a HDPE (plastic) bottle with screw cap

- 120 soft capsules in a HDPE (plastic) bottle with screw cap

- 180 soft capsules in a HDPE (plastic) bottle with screw cap

Ofev 100 mg soft capsules

Ofev 100 mg soft capsules are available in the following pack-sizes:

- 30 × 1 soft capsules in aluminium/aluminium perforated unit dose blisters

- 60 × 1 soft capsules in aluminium/aluminium perforated unit dose blisters

Ofev 150 mg soft capsules

Ofev 150 mg soft capsules are available in the following pack-sizes:

- 30 × 1 soft capsules in aluminium/aluminium perforated unit dose blisters

- 60 × 1 soft capsules in aluminium/aluminium perforated unit dose blisters

Not all pack sizes may be marketed.

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

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Boehringer Ingelheim International GmbH

Binger Strasse 17355216 Ingelheim am Rhein

Germany

Ofev 25 mg soft capsules

EU/1/14/979/009

EU/1/14/979/010

EU/1/14/979/011

EU/1/14/979/012

Ofev 100 mg soft capsules

EU/1/14/979/001

EU/1/14/979/002

Ofev 150 mg soft capsules

EU/1/14/979/003

EU/1/14/979/004

Date of first authorisation: 15 January 2015

Date of latest renewal: 23 September 2019

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

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