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Gastrointestinal disorders: Diarrhoea: In the clinical trials (see Pharmacology: Pharmacodynamics 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 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 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 gastrointestinal adverse reactions (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 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 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.
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 Dosage & Administration). 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 and 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, alkaline phosphatase (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 > 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 (see Dosage & Administration). 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 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: Vascular endothelial growth factor receptor (VEGFR) inhibition might be associated with an increased risk of bleeding.
In the clinical trials in adult patientswith 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.
Cases of haemorrhage have been reported in post-marketing period (including patients with or without anticoagulant therapy or other drugs that could cause bleeding). 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: 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.
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 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 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: In the clinical trials, the frequency of patients with perforation was up to 0.3% in both treatment groups. Due to the mechanism of action 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.
Hypertension: Administration of OFEV may increase blood pressure. Systemic blood pressure should be measured periodically and as clinically indicated.
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 OFEV was discontinued. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.
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: Concomitant treatment of nintedanib with pirfenidone was investigated in a parallel group design study in Japanese patients with IPF. Twenty four patients were treated for 28 days with 150 mg nintedanib twice daily (13 patients received nintedanib on top of chronic treatment with standard doses of pirfenidone; 11 patients received nintedanib alone). Due to the short duration of concomitant exposure and low number of patients the benefit/risk of the co-administration with pirfenidone has not been established.
Effect on QT interval: No evidence of QT prolongation was observed for nintedanib in the clinical trial programme (see Pharmacology: Pharmacodynamics under Actions). As some other tyrosine kinase inhibitors are known to exert an effect on QT, caution should be exercised when administered nintedanib in patients who may develop QTc prolongation.
Allergic reaction: Dietary soya products are known to cause allergic reactions including severe anaphylaxis in persons with soya allergy. Patients with known allergy to peanut protein carry an enhanced risk for severe reactions to soya preparations.
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.
