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Gastrointestinal-Disorders: NSCLC: 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 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 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.
IPF/chronic fibrosing ILDs with a progressive phenotype/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 OFEV and placebo, respectively. Diarrhoea led to dose reduction of OFEV in 10.7% of the patients and to discontinuation of nintedanib 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 OFEV and placebo, respectively. Diarrhoea led to dose reduction of OFEV in 16.0% of the patients and to discontinuation of 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 OFEV and placebo, respectively. Diarrhoea led to dose reduction of OFEV in 22.2% of the patients and to discontinuation of 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. 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 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 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 OFEV discontinuation were 0.3% and 0.9%, respectively. In the SENSCIS trial, the frequency of nausea and vomiting leading to 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 OFEV should be discontinued.
Diarrhoea and vomiting may lead to dehydration with or without electrolyte disturbances, which may progress to renal function impairment.
Hypertension: Administration of OFEV may increase blood pressure. Systemic blood pressure should be measured periodically and as clinically indicated.
The use of VEGFR inhibitors may promote the formation of aneurysm and/or artery dissection. Serious cases of artery dissection have been reported in patients using VEGFR TKIs, including nintedanib. Before initiating OFEV, this risk should be carefully considered in patients with risk factors such as poorly controlled hypertension or a history of aneurysm.
Neutropenia and Sepsis: NSCLC: A higher frequency of neutropenia of CTCAE grade > 3 was observed in patients treated with 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: NSCLC: Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A; see Dosage & Administration, Pharmacology: Pharmacokinetics under Actions). Limited safety data are available in 9 patients with hepatocellular carcinoma and moderate hepatic impairment classified as Child Pugh B. Although no unexpected safety findings were reported in these patients, the data are insufficient to support a recommendation for treatment of patients with moderate hepatic impairment. The efficacy of nintedanib has not been investigated in patients with moderate hepatic impairment (Child Pugh B). The safety, efficacy and pharmacokinetics of nintedanib have not been studied in patients with severe hepatic impairment (Child Pugh C). Treatment with nintedanib is not recommended in patients with moderate or severe hepatic impairment (see Dosage & Administration).
Cases of drug-induced liver injury have been observed with nintedanib treatment. In the post‐marketing 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 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 OFEV is continued as mono-therapy after discontinuation of docetaxel.
If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with 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 OFEV should be interrupted. Unless there is an alternative cause established, 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.
IPF/chronic fibrosing ILDs with a progressive phenotype/SSc-ILD: 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. Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A). Patients with mild hepatic impairment (Child Pugh A) should be treated with a reduced dose of OFEV (see Dosage & Administration, Pharmacology: Pharmacokinetics under Actions).
Cases of drug-induced liver injury have been observed with nintedanib treatment. In the post‐marketing 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 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-glutamyltransferase (GGT)) and bilirubin were reversible upon dose reduction or interruption in the majority of cases. If transaminase (AST or ALT) elevations > 3x 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 (150 mg twice daily) or reintroduced at a reduced dose (100 mg twice daily) which subsequently may be increased to the full dose. 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.
Patients with a low body weight (<65Kg), Asian and female patients have a higher risk of elevations in liver enzymes. Nintedanib exposure increased linearly with patient age, which may 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.
Special populations: NSCLC: In study 1199.13 (LUME-Lung 1), there was a higher frequency of serious adverse events in patients treated with nintedanib plus docetaxel with a body weight of less than 50 kg compared to patients with a weight ≥ 50 kg; however the number of patients with a body weight of less than 50 kg was small. Therefore close monitoring is recommended in patients weighing < 50 kg.
Renal Function: Cases of renal impairment/failure, in some cases with fatal outcome, have been reported with nintedanib use (see Adverse Reactions). 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 Dose adjustments under Dosage & Administration).
Haemorrhage: NSCLC: VEGFR inhibition might be associated with an increased risk of bleeding. In the clinical trial (LUME-Lung 1) with 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 ¾ bleeding events, the benefits and risks of continuing treatment with OFEV should be carefully weighed and discontinuation of OFEV may be considered. If treatment with 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 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 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 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 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 develop thromboembolic events during treatment and who required anticoagulant treatment were allowed to continue 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.
IPF/chronic fibrosing ILDs with a progressive phenotype/SSc-ILD: VEGFR inhibition might be associated with an increased risk of bleeding.
In the clinical trials in adult patients with OFEV, the frequency of patients who experienced bleeding adverse events 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).
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. Therefore these patients should only be treated with 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.
NSCLC: 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.
IPF/chronic fibrosing ILDs with a progressive phenotype/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 (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 and the SENSCIS trial, myocardial infarction was observed with low frequency: OFEV 0.9% versus placebo 0.9% for INBUILD; OFEV 0% versus placebo 0.7% for SENSCIS.
Venous thromboembolism: NSCLC: Patients treated with OFEV have an increased risk of venous thromboembolism including deep vein thrombosis. Patients should be closely monitored for thromboembolic events. OFEV should be discontinued in patients with life-threatening venous thromboembolic reactions.
IPF/chronic fibrosing ILDs with a progressive phenotype/SSc-ILD: In the clinical trials, no increased risk of venous thromboembolism was observed in OFEV treated patients. Due to the mechanism of action of nintedanib patients might have an increased risk of thromboembolic events.
Gastrointestinal perforations and ischaemic colitis: Due to the mechanism of action nintedanib patients might have an increased risk of gastrointestinal perforations and ischaemic colitis. 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.
NSCLC: The frequency of gastrointestinal perforation was comparable between the treatment arms in the LUME-Lung 1 study. Particular caution should be exercised when treating patients with previous abdominal surgery or a recent history of a hollow organ perforation.
IPF/chronic fibrosing ILDs with a progressive phenotype/SSc-ILD: In the clinical trials, no increased risk of gastrointestinal perforation was observed in OFEV treated patients. Particular caution should be exercised when treating patients with previous abdominal surgery, a recent history of a hollow organ perforation, previous history of peptic ulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs.
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 proteinuria after OFEV was discontinued. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.
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 OFEV should therefore only be initiated or - in case of perioperative interruption - resumed based on clinical judgment of adequate wound healing.
Effect on QT interval: No QT prolongation was observed for nintedanib in the clinical trial program (see Pharmacology: Pharmacodynamics under Actions). As several other tyrosine kinase inhibitors are known to exert an effect on QT, caution should be exercised when administering nintedanib in patients who may develop QTc prolongation.
Soya lecithin: OFEV soft capsules contain soya lecithin which may cause allergic reactions including severe anaphylaxis in persons with soya allergy. Patients with known allergy to peanut protein carry an enhanced risk for severe reactions to soya preparations (see Contraindications).
EFFECTS ON ABILITY TO DRIVE AND USE 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 OFEV.
