Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Boehringer Ingelheim International GmbH, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany
Hypersensitivity to nintedanib, to peanut or soya, or to any of the excipients listed in section 6.1.
Diarrhoea was the most frequently reported gastro-intestinal adverse reaction and appeared in close temporal relationship with the administration of docetaxel (see section 4.8). In the clinical trial LUME-Lung 1 (see section 5.1), the majority of patients had mild to moderate diarrhoea. Serious cases of diarrhoea leading to dehydration and electrolyte disturbances have been reported with nintedanib in the post-marketing period. Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, for example loperamide, and may require interruption, dose reduction or discontinuation of therapy with Vargatef (see section 4.2).
Nausea and vomiting, mostly of mild to moderate severity, were frequently reported gastrointestinal adverse reactions (see section 4.8). Interruption, dose reduction or discontinuation of therapy with Vargatef (see section 4.2) may be required despite appropriate supportive care. Supportive care for nausea and vomiting may include medicinal products with anti-emetic properties, e.g. glucocorticoids, anti-histamines or 5-HT3 receptor antagonists and adequate hydration.
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. Interruption, dose reduction or discontinuation of therapy with Vargatef may be required (see section 4.2).
A higher frequency of neutropenia of CTCAE grade ≥3 was observed in patients treated with Vargatef 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.
Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A; see sections 4.2 and 5.2). 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 Vargatef is not recommended in patients with moderate or severe hepatic impairment (see section 4.2).
Cases of drug-induced liver injury have been observed with nintedanib treatment, including severe liver injury with fatal outcome. Elevation 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 before initiation of the combination treatment with Vargatef 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 Vargatef is continued as monotherapy after discontinuation of docetaxel.
If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with Vargatef may be required (see section 4.2). 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; total bilirubin ≥2 x ULN and ALKP <2 x ULN) treatment with Vargatef should be interrupted. Unless there is an alternative cause established, Vargatef should be permanently discontinued (see section 4.2).
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 section 5.2). Close monitoring is recommended in patients with these risk factors.
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).
VEGFR inhibition might be associated with an increased risk of bleeding. In the clinical trial (LUME-Lung 1; see section 5.1) with Vargatef, the frequency of bleeding in both treatment arms was comparable (see section 4.8). Mild to moderate epistaxis represented the most frequent bleeding event. The majority of fatal bleeding events were tumour-associated. There were no imbalances of respiratory or fatal bleedings and no intracerebral bleeding was reported.
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 Vargatef.
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 (for clinical trials' data, see also ‘Therapeutic anticoagulation’ below). In case of bleeding, dose adjustment, interruption or discontinuation should be considered based on clinical judgement (see section 4.2). Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous system organs, with the most frequent being respiratory.
There are no data available from clinical trials for patients with inherited predisposition to bleeding or for patients receiving a full dose of anticoagulative treatment prior to start of treatment with Vargatef (for post-marketing experience, see ‘Haemorrhage’ above). 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 Vargatef 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, international normalised ratio (INR), and clinical bleeding episodes.
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 Vargatef 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 Vargatef.
Patients treated with Vargatef have an increased risk of venous thromboembolism including pulmonary embolism and deep vein thrombosis. Patients should be closely monitored for thromboembolic events. Caution should be used especially in patients with additional risk factors for thromboembolic events. Vargatef should be discontinued in patients with life-threatening venous thromboembolic reactions.
The frequency of arterial thromboembolic events was comparable between the two treatment arms in the phase 3 trial 1199.13 (LUME-Lung 1). Patients with a recent history of myocardial infarction or stroke were excluded from this trial. However, an increased frequency of arterial thromboembolic events was observed in patients with idiopathic pulmonary fibrosis (IPF) when treated with nintedanib monotherapy. 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.
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Vargatef, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
The frequency of gastrointestinal perforation was comparable between the treatment arms in the clinical trial. However, based on the mechanism of action patients treated with Vargatef may have an increased risk of gastrointestinal perforations. Cases of gastrointestinal perforations and ischaemic colitis, some of which were fatal, have been reported in the post-marketing period under nintedanib. Particular caution should be exercised when treating patients with previous abdominal surgery or a recent history of a hollow organ perforation. Vargatef should therefore only be initiated at least 4 weeks after major surgery. Therapy with Vargatef should be permanently discontinued in patients who develop gastrointestinal perforation. In patients who develop ischaemic colitis Vargatef should be discontinued, and exceptionally, Vargatef can be reintroduced after complete resolution of ischaemic colitis and careful assessment of patient’s condition and other risk factors.
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 Vargatef was discontinued. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.
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.
Based on the mechanism of action nintedanib may impair wound healing. No increased frequency of impaired wound healing was observed in the LUME-Lung 1 trial. No dedicated trials investigating the effect of nintedanib on wound healing were performed. Treatment with Vargatef should therefore only be initiated or – in case of perioperative interruption – resumed based on clinical judgement of adequate wound healing.
No QT prolongation was observed for nintedanib in the clinical trial program (see section 5.1). 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.
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.
In trial 1199.13 (LUME-Lung 1), there was a higher frequency of SAEs 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
Interaction studies have only been performed in adults.
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 nintedanib, potent P-gp inhibitors (e.g. ketoconazole or erythromycin) 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 Vargatef (see section 4.2).
Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decrease exposure to nintedanib. Co-administration with nintedanib should be carefully considered.
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 of nintedanib with docetaxel (75 mg/m²) did not alter the pharmacokinetics of either medicinal product to a relevant extent.
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).
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 Vargatef and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of Vargatef. 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.
There is no information on the use of Vargatef in pregnant women, but preclinical 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 should not be used during pregnancy unless the clinical condition requires treatment. Pregnancy testing should be conducted at least prior to treatment with Vargatef. Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy with Vargatef.
If the patient becomes pregnant while receiving Vargatef, she should be apprised of the potential hazard to the foetus. Termination of the treatment with Vargatef should be considered.
There is no information on the excretion of nintedanib and its metabolites in human milk. Preclinical 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 breast-fed child cannot be excluded. Breast-feeding should be discontinued during treatment with Vargatef.
Based on preclinical investigations there is no evidence for impairment of male fertility (see section 5.3). There are no human or animal data on potential effects of nintedanib on female fertility available.
Vargatef 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 Vargatef.
The safety data provided in the sections below are based on the global, double-blind randomised pivotal phase 3 trial 1199.13 (LUME-Lung 1) comparing treatment with nintedanib plus docetaxel against placebo plus docetaxel in patients with locally advanced, or metastatic, or recurrent NSCLC after first-line chemotherapy and based on data observed during the post-marketing period. The most frequently reported adverse drug reactions (ADRs) specific for nintedanib were diarrhoea, increased liver enzyme values (ALT and AST) and vomiting. Table 3 provides a summary of the adverse reactions by System Organ Class (SOC). For the management of selected adverse reactions, see section 4.4. Information about selected adverse reactions observed from the LUME-Lung 1 trial are described below.
Table 3 summarizes the frequencies of adverse drug reactions that were reported in the pivotal trial LUME-Lung 1 for patients with NSCLC of adenocarcinoma tumour histology (n=320) or from the post-marketing period. The following terms are used to rank the ADRs by frequency: 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). Within each frequency grouping adverse reactions are presented in order of decreased seriousness.
Table 3. Summary of ADRs per frequency category:
| System Organ Class | Very common (≥1/10) | Common (≥1/100 <1/10) | Uncommon (≥1/1 000 <1/100) | Not known |
|---|---|---|---|---|
| Infections and infestations | Febrile neutropenia, Abscesses, Sepsis | |||
| Blood and lymphatic system disorders | Neutropenia (includes febrile neutropenia) | Thrombocytopenia | ||
| Metabolism and nutrition disorders | Decreased appetite, Electrolyte imbalance | Dehydration, Weight decreased | ||
| Nervous system disorders | Peripheral neuropathy | Headache1 | Posterior reversible encephalopathy syndrome | |
| Cardiac disorders | Myocardial infarction (see section 4.4) | |||
| Vascular disorders | Bleeding1 (see section 4.4) | Venous thromboembolism3), Hypertension | Aneurysms and artery dissections | |
| Gastrointestinal disorders | Diarrhoea, Vomiting, Nausea, Abdominal pain | Perforation1 Pancreatitis2 | Colitis | |
| Hepatobiliary disorders | Alanine aminotransferase (ALT) increased, Aspartate aminotransferase (AST) increased, Blood alkaline phosphatase (ALKP) increased | Hyperbilirubinaemia, Gamma-glutamyltran sferase (GGT) increased | Drug-induced liver injury | |
| Skin and subcutaneous tissue disorders | Mucositis (including stomatitis), Rash, Alopecia1 | Pruritus | ||
| Renal and urinary disorders | Proteinuria1 | Renal failure (see section 4.4) |
1 In clinical trials the frequency was not increased in patients treated with nintedanib plus docetaxel as compared to placebo plus docetaxel.
2 Events of pancreatitis have been reported in patients taking nintedanib for the treatment of IPF and NSCLC. The majority of these events were reported for patients in the IPF indication.
3 Cases of pulmonary embolism have been reported.
Diarrhoea occurred in 43.4% (≥ grade 3: 6.3%) of adenocarcinoma patients in the nintedanib arm. The majority of adverse reactions appeared in close temporal relationship with the administration of docetaxel. Most patients recovered from diarrhoea following treatment interruption, anti-diarrhoeal therapy and nintedanib dose reduction.
For recommended measures and dosing adjustments in case of diarrhoea, see sections 4.4 and 4.2, respectively.
Liver-related adverse reactions occurred in 42.8% of nintedanib-treated patients. Approximately one third of these patients had liver-related adverse reactions of ≥ grade 3 severity. In patients with increased liver parameters, the use of the established stepwise dose reduction scheme was the appropriate measure and discontinuation of treatment was only necessary in 2.2% of patients. In the majority of patients, elevations of liver parameters were reversible.
For information about special populations, recommended measures and dosing adjustments in case of liver enzyme and bilirubin elevations, see sections 4.4 and 4.2, respectively.
Sepsis and febrile neutropenia have been reported as subsequent complications of neutropenia. The rates of sepsis (1.3%) and febrile neutropenia (7.5%) were increased under treatment with nintedanib as compared to the placebo arm. It is important that the patient’s blood counts are monitored during therapy, in particular during the combination treatment with docetaxel (see section 4.4).
In the post-marketing period non-serious and serious bleeding events, some of which fatal, have been reported, including patients with or without anticoagulant therapy or other medicinal products that could cause bleeding. Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous system organs, with the most frequent being respiratory (see also section 4.4).
As expected via its mechanism of action perforation might occur in patients treated with nintedanib. However, the frequency of patients with gastrointestinal perforation was low.
Peripheral neuropathy is also known to occur with docetaxel treatment. Peripheral neuropathy was reported in 16.5% of patients in the placebo arm and in 19.1% of patients in the nintedanib arm.
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 the national reporting system listed in Appendix V.
Not applicable.
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