4.1. Therapeutic indications

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

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

Ofev is indicated in 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).

4.2. Posology and method of administration

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

Weight range

Ofev dose

Ofev reduced dose*

13.5** - 22.9 kg

50 mg (two 25 mg capsules) twice daily

25 mg (one 25 mg capsule) twice daily

23.0 - 33.4 kg

75 mg (three 25 mg capsules) twice daily

50 mg (two 25 mg capsules) twice daily

33.5 - 57.4 kg

100 mg (one 100 mg capsule or four 25 mg capsules) twice daily

75 mg (three 25 mg capsules) twice daily

57.5 kg and above

150 mg (one 150 mg capsule or six 25 mg capsules) twice daily

100 mg (one 100 mg capsule or four 25 mg capsules) twice daily

* 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 more information 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.

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

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. Nintedanib has not been studied in patients with a weight below 13.5 kg and therefore, it is not recommended in this population (see section 5.1).

Method of administration

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

4.3. Contraindications

• Pregnancy (see section 4.6)

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

4.4. Special warnings and precautions for use

Gastrointestinal disorders

Diarrhoea

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.

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

P-glycoprotein (P-gp)

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

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

Cytochrome (CYP)-enzymes

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

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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception

Nintedanib may cause foetal harm in humans (see section 5.3). Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Ofev and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of Ofev. Nintedanib does not relevantly affect the plasma exposure of ethinylestradiol and levonorgestrel (see section 5.2). The efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhoea or other conditions where the absorption may be affected. Women taking oral hormonal contraceptives experiencing these conditions should be advised to use an alternative highly effective contraceptive measure.

Pregnancy

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

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

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

Breast-feeding

There is no information on the excretion of nintedanib and its metabolites in human milk.

Pre-clinical studies showed that small amounts of nintedanib and its metabolites (≤ 0.5% of the administered dose) were secreted into milk of lactating rats. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Ofev.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

For the management of selected adverse reactions see section 4.4.

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

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 paediatric patients.

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

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

Based on preclinical findings, bone, growth and teeth development were monitored as potential risks in the paediatric clinical trial (see section 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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is no specific antidote or treatment for 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.