Ofev Special Precautions

Gastrointestinal Disorders: Oncology: Diarrhoea: Diarrhoea was the most frequently reported gastro-intestinal event and appeared in close temporal relationship with the administration of docetaxel (see Adverse Reactions). In the clinical trial LUME-Lung 1 (see Pharmacology: Pharmacodynamics: Clinical trials under Actions), the majority of patients had mild to moderate diarrhoea. 6.3% of the patients had diarrhoea of grade ≥3 in combination treatment compared to 3.6% treated with docetaxel alone. Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require interruption, dose reduction or discontinuation of therapy with Nintedanib esilate (Ofev) (see Dosage & Administration).
Nausea and vomiting: Nausea and vomiting, mostly of mild to moderate severity, were frequently reported gastrointestinal adverse events (see Adverse Reactions). If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction, treatment interruption or discontinuation of therapy with Nintedanib esilate (Ofev) (see Dosage & Administration) may be required.
Diarrhoea and vomiting may lead to dehydration with or without electrolyte disturbances which may progress to renal function impairment. In the event of dehydration, administration of electrolytes and fluids is required. Plasma levels of electrolytes should be monitored, if relevant gastrointestinal adverse events occur.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Diarrhoea: In the clinical trials (see Pharmacology: Pharmacodynamics: Clinical trials under Actions), diarrhoea was the most frequent gastro-intestinal event reported. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. In the INPULSIS trials in patients with IPF, diarrhoea was reported in 62.4% versus 18.4% of patients treated with Nintedanib esilate (Ofev) and placebo, respectively. Diarrhoea led to dose reduction in 10.7% of the patients and to discontinuation of Nintedanib esilate (Ofev) in 4.4% of the patients. In the INBUILD trial in patients with other chronic fibrosing ILDs with a progressive phenotype, diarrhoea was reported in 66.9% versus 23.9% of patients treated with Nintedanib esilate (Ofev) and placebo, respectively. Diarrhoea led to dose reduction of Nintedanib esilate (Ofev) in 16.0% of the patients and to discontinuation of Nintedanib esilate (Ofev) in 5.7% of the patients. In the SENSCIS trial in patients with SSc-ILD, diarrhoea was reported in 75.7% versus 31.6% of patients treated with Nintedanib esilate (Ofev) and placebo, respectively. Diarrhoea led to dose reduction of Nintedanib esilate (Ofev) in 22.2% of the patients and to discontinuation of Nintedanib esilate (Ofev) in 6.9% of the patients (see Adverse Reactions).
Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require dose reduction or treatment interruption. Nintedanib esilate (Ofev) treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with Nintedanib esilate (Ofev) should be discontinued.
Nausea and vomiting: Nausea and vomiting were frequently reported adverse events (see Adverse Reactions). In most patients with nausea and vomiting, the event was of mild to moderate intensity. In the INPULSIS trials, nausea led to discontinuation of Nintedanib esilate (Ofev) in 2.0% of patients and vomiting led to discontinuation in 0.8% of the patients. In the INBUILD trial, the frequency of nausea and vomiting leading to Nintedanib esilate (Ofev) discontinuation were 0.3% and 0.9%, respectively. In the SENSCIS trial, the frequency of nausea and vomiting leading to Nintedanib esilate (Ofev) discontinuation were 2.1% and 1.4%, respectively.
If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction or treatment interruption may be required. The treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe symptoms therapy with Nintedanib esilate (Ofev) should be discontinued.
Diarrhoea and vomiting may lead to dehydration with or without electrolyte disturbances which may progress to renal function impairment.
Neutropenia and Sepsis: Oncology: A higher frequency of neutropenia of CTCAE grade >3 was observed in patients treated with Nintedanib esilate (Ofev) in combination with docetaxel as compared to treatment with docetaxel alone. Subsequent complications such as sepsis or febrile neutropenia have been observed.
Blood counts should be monitored during therapy, in particular during the combination treatment with docetaxel. Frequent monitoring of complete blood counts should be performed at the beginning of each treatment cycle and around the nadir for patients receiving treatment with nintedanib in combination with docetaxel, and as clinically indicated after the administration of the last combination cycle.
Hepatic Function: The safety and efficacy of Nintedanib esilate (Ofev) has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore treatment with Nintedanib esilate (Ofev) is not recommended in such patients.
Oncology: Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A; see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cases of drug-induced liver injury have been observed with nintedanib treatment. In the postmarketing period, severe liver injury with fatal outcome has been reported. Elevations of liver enzymes (ALT, AST, ALKP, gamma-glutamyltransferase (GGT)) and bilirubin were reversible upon dose reduction or interruption in the majority of cases.
Transaminase, ALKP and bilirubin levels should be investigated upon initiation of the combination treatment with Nintedanib esilate (Ofev) plus docetaxel. The values should be monitored as clinically indicated or periodically during treatment, i.e. in the combination phase with docetaxel at the beginning of each treatment cycle and monthly in case Nintedanib esilate (Ofev) is continued as monotherapy after discontinuation of docetaxel.
If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with Nintedanib esilate (Ofev) may be required (see Table 13 under Dosage & Administration). Alternative causes of the liver enzyme elevations should be investigated and respective action should be taken as necessary.
In case of specific changes in liver values (AST/ALT >3 x ULN in conjunction with bilirubin ≥2 x ULN and ALKP <2 x ULN) treatment with Nintedanib esilate (Ofev) should be interrupted. Unless there is an alternative cause established, Nintedanib esilate (Ofev) should be permanently discontinued (see Table 13 under Dosage & Administration).
Female and Asian patients have a higher risk of elevations in liver enzymes.
Nintedanib exposure increased linearly with patient age and was inversely correlated to weight which may also result in a higher risk of developing liver enzyme elevations (see Pharmacology: Pharmacokinetics under Actions). Close monitoring is recommended in patients with these risk factors.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A). Adult patients with mild hepatic impairment (Child Pugh A) should be treated with a reduced dose of Nintedanib esilate (Ofev) (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cases of drug-induced liver injury have been observed with nintedanib treatment. In the postmarketing period, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcome, have been reported. The majority of hepatic events occur within the first three months of treatment. Therefore, hepatic transaminase and bilirubin levels should be investigated upon initiation of treatment with Nintedanib esilate (Ofev), at regular intervals during the first three months of treatment and periodically thereafter (e.g. at each patient visit) or as clinically indicated.
Elevations of liver enzymes (ALT, AST, ALKP, gamma-glutamyl-transferase (GGT)) and bilirubin were reversible upon dose reduction or interruption in the majority of cases. If transaminase (AST or ALT) elevations >3 x upper limit of normal (ULN) are measured, dose reduction or interruption of the therapy with Nintedanib esilate (Ofev) is recommended and the patient should be monitored closely. Once transaminases have returned to baseline values, treatment with Nintedanib esilate (Ofev) may be re-increased to the full dose (150 mg twice daily) or reintroduced at a reduced dose daily (100 mg twice daily) which subsequently may be increased to the full dose (see Dosage & Administration). If any liver test elevations are associated with clinical signs or symptoms of liver injury, e.g. jaundice, treatment with Nintedanib esilate (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 in liver enzymes.
Nintedanib exposure increased linearly with patient age, which may also result in a higher risk of developing liver enzyme elevations (see Pharmacology: Pharmacokinetics under Actions).
Close monitoring is recommended in patients with these risk factors.
Haemorrhage: Oncology: VEGFR inhibition might be associated with an increased risk of bleeding. In the clinical trial (LUME-Lung 1) with Nintedanib esilate (Ofev), the frequency of bleeding in both treatment arms was comparable. Mild to moderate epistaxis represented the most frequent bleeding event. There were no imbalances of respiratory or fatal bleedings and no intracerebral bleeding was reported. The majority of fatal bleeding events were tumour-associated.
In the post-marketing period non-serious and serious bleeding events, some of which were fatal, have been observed. In patients who experience grade 3/4 bleeding events, the benefits and risks of continuing treatment with Nintedanib esilate (Ofev) should be carefully weighed and discontinuation of Nintedanib esilate (Ofev) may be considered. If treatment with Nintedanib esilate (Ofev) is resumed, a reduced daily dose is recommended (see Table 12 under Dosage & Administration).
Patients with recent pulmonary bleeding (>2.5 mL of red blood) as well as patients with centrally located tumours with radiographic evidence of local invasion of major blood vessels or radiographic evidence of cavitary or necrotic tumours have been excluded from clinical trials. Therefore, it is not recommended to treat these patients with Nintedanib esilate (Ofev).
Brain metastasis: Stable brain metastasis: No increased frequency of cerebral bleeding in patients with adequately pre-treated brain metastases which were stable for ≥4 weeks before start of treatment with Nintedanib esilate (Ofev) was observed. However, such patients should be closely monitored for signs and symptoms of cerebral bleeding.
Active brain metastasis: Patients with active brain metastasis were excluded from clinical trials and are not recommended for treatment with Nintedanib esilate (Ofev).
Therapeutic anticoagulation: There are no data available for patients with inherited predisposition to bleeding or for patients receiving a full dose of anticoagulative treatment prior to start of treatment with Nintedanib esilate (Ofev). In patients on chronic low dose therapy with low molecular weight heparins or acetylsalicylic acid, no increased frequency of bleeding was observed. Patients who developed thromboembolic events during treatment and who required anticoagulant treatment were allowed to continue Nintedanib esilate (Ofev) and did not show an increased frequency of bleeding events. Patients taking concomitant anticoagulation, such as warfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, INR, or clinical bleeding episodes.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): VEGFR inhibition might be associated with an increased risk of bleeding.
In the clinical trials in adult patients with Nintedanib esilate (Ofev), the frequency of patients who experienced bleeding adverse events was slightly higher in patients treated with Nintedanib esilate (Ofev) or comparable between the treatment arms (Nintedanib esilate (Ofev) 10.3% versus placebo 7.8% for INPULSIS; Nintedanib esilate (Ofev) 11.1% versus placebo 12.7% for INBUILD; Nintedanib esilate (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 (Nintedanib esilate (Ofev) 1.3% versus placebo 1.4% for INPULSIS; Nintedanib esilate (Ofev) 0.9% versus placebo 1.5% for INBUILD; Nintedanib esilate (Ofev) 1.4% versus placebo 0.7% for SENSCIS). 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 clinical trials. Therefore, these patients should only be treated with Nintedanib esilate (Ofev) if the anticipated benefit outweighs the potential risk. In the post-marketing period non-serious and serious bleeding events, some of which were fatal, have been observed.
Arterial thromboembolic events: Use caution when treating patients with a higher cardiovascular risk including known coronary artery disease. Treatment interruption should be considered in patients who develop signs or symptoms of acute myocardial ischaemia.
Oncology: The frequency of arterial thromboembolic events was comparable between the two treatment arms in the phase III study 1199.13 (LUME-Lung 1). Patients with a recent history of myocardial infarction or stroke were excluded from this study. However, an increased frequency of arterial thromboembolic events was observed in patients with Idiopathic Pulmonary fibrosis (IPF) when treated with nintedanib monotherapy.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): Patients with a recent history of myocardial infarction or stroke were excluded from the clinical trials.
In the clinical trials in adult patients, arterial thromboembolic events were infrequently reported (Nintedanib esilate (Ofev) 2.5% versus placebo 0.7% for INPULSIS: Nintedanib esilate (Ofev) 0.9% versus placebo 0.9% for INBUILD; Nintedanib esilate (Ofev) 0.7% versus placebo 0.7% for SENSCIS). In the INPULSIS trials, a higher percentage of patients experienced myocardial infarctions in the Nintedanib esilate (Ofev) group (1.6%) compared to the placebo group (0.5%) while adverse events reflecting ischaemic heart disease were balanced between the Nintedanib esilate (Ofev) and placebo groups. In the INBUILD and the SENSCIS trial myocardial infarction was observed with low frequency: Nintedanib esilate (Ofev) 0.9% versus placebo 0.9% for INBUILD; Nintedanib esilate (Ofev) 0% versus placebo 0.7% for SENSCIS.
Venous thromboembolism: Oncology: Patients treated with Nintedanib esilate (Ofev) have an increased risk of venous thromboembolism including deep vein thrombosis. Patients should be closely monitored for thromboembolic events. Nintedanib esilate (Ofev) should be discontinued in patients with life-threatening venous thromboembolic reactions.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): In the clinical trials no increased risk of venous thromboembolism was observed in Nintedanib esilate (Ofev) treated patients. Due to the mechanism of action of nintedanib patients might have an increased risk of thromboembolic events.
Gastrointestinal perforations: Oncology: The frequency of gastrointestinal perforation was comparable between the treatment arms in the LUME-Lung 1 study. Due to the mechanism of action nintedanib patients might have an increased risk of gastrointestinal perforations. Cases of gastrointestinal perforations, 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 or a recent history of a hollow organ perforation. Nintedanib esilate (Ofev) should therefore only be initiated at least 4 weeks after major, incl. abdominal, surgery. Therapy with Nintedanib esilate (Ofev) should be permanently discontinued in patients who develop gastrointestinal perforation.
Idiopathic Pulmonary Fibrosis (IPF), other chronic fibrosing Interstitial Lung Diseases (ILDs) with a progressive phenotype and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD): In the clinical trials no increased risk of gastrointestinal perforation was observed in Nintedanib esilate (Ofev) treated patients. Due to the mechanism of action nintedanib patients might have an increased risk of gastrointestinal perforations. Cases of gastrointestinal perforations, 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, or a recent history of a hollow organ perforation, previous history of peptic ulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs. Nintedanib esilate (Ofev) should therefore only be initiated at least 4 weeks after major, incl. abdominal, surgery. Therapy with Nintedanib esilate (Ofev) should be permanently discontinued in patients who develop gastrointestinal perforation.
Nephrotic range proteinuria: Very few cases of nephrotic range proteinuria have been reported post-marketing. Histological findings in individual cases were consistent with glomerular microangiopathy with or without renal thrombi. Reversal of symptoms has been observed after Nintedanib esilate (Ofev) was discontinued. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.
Posterior reversible encephalopathy syndrome (PRES): Very few cases of posterior reversible encephalopathy syndrome (PRES) have been reported postmarketing.
PRES is a neurological disorder which can present with headache, visual disturbances, seizure, lethargy, confusion and other neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES.
If PRES is suspected, nintedanib treatment must be discontinued. The safety of reinitiating nintedanib therapy in patients previously experiencing PRES is not known.
Wound healing complication: Based on the mechanism of action nintedanib may impair wound healing. No increased frequency of impaired wound healing was observed in the clinical trials. No dedicated studies investigating the effect of nintedanib on wound healing were performed. Treatment with Nintedanib esilate (Ofev) should therefore only be initiated or in case of perioperative interruption resumed based on clinical judgement of adequate wound healing.
Special Populations: Oncology: In the study 1199.13 (LUME-Lung 1), there was a higher frequency of serious adverse events in patients treated with Nintedanib esilate (Ofev) plus docetaxel with a body weight of less than 50 kg compared to patients with a weight ≥50 kg; however the number of patients with a body weight of less than 50 kg was small. Therefore, close monitoring is recommended in patients weighing <50 kg.
Soya lecithin: Nintedanib esilate (Ofev) soft capsules contain soya lecithin.
If the patient is allergic to peanut or soya, do not use this medicinal product.
Driving and Using Machines: No studies of the effects on the ability to drive and use machines have been performed.
Patients should be advised to be cautious when driving or using machines during treatment with Nintedanib esilate (Ofev).