英文药名：Vargatef（nintedanib soft capsules）
Table 2: Recommended dose adjustments for Vargatef (nintedanib) in case of AST and/or ALT and bilirubin elevations
ALKP: Alkaline phosphatase; ULN: Upper limit normal
The safety and efficacy of Vargatef in children aged 0-18 years have not been established. No data are available.
Elderly patients (≥ 65 years)
No overall differences in safety and efficacy were observed for elderly patients.
In the pivotal study 1199.13, 85 patients (12.9 % of the patients with adenocarcinoma histology) were ≥ 70 years of age (median age: 72 years, range: 70 - 80 years) (see section 5.1). No adjustment of the initial dosing is required on the basis of a patient's age (see section 5.2).
Race and body weight
Based on population pharmacokinetic (PK) analyses, no a priori dose adjustments of Vargatef are necessary (see section 5.2). Safety data for Black and African American patients are limited.
Less than 1 % of a single dose of nintedanib is excreted via the kidney (see section 5.2). Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (< 30 ml/min creatinine clearance).
Nintedanib is predominantly eliminated via biliary/faecal excretion (> 90 %; see section 5.2). No adjustment of the starting dose is needed for patients with mild hepatic impairment based on clinical data (Child Pugh A; see section 4.4). The safety, efficacy, and pharmacokinetics of nintedanib have not been investigated in patients with hepatic impairment classified as Child Pugh B and C. Therefore, treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Vargatef is not recommended.
Method of administration
Vargatef capsules must be taken orally, preferably with food, swallowed whole with water, and must not be chewed or crushed.
Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
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. 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.
Neutropenia and sepsis
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.
The safety and efficacy of nintedanib has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore treatment with Vargatef is not recommended in such patients (see sections 5.2).
Administration of nintedanib was associated with an elevation of liver enzymes (ALT, AST, ALKP) or bilirubin, with a potentially higher risk for female patients. These increases were reversible in the majority of cases.
Transaminase, ALKP and bilirubin levels should be investigated before the 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).
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.
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 Vargatef. 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 normalized 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 deep vein thrombosis. Patients should be closely monitored for thromboembolic events. Vargatef should be discontinued in patients with life-threatening venous thromboembolic reactions.
Arterial thromboembolic events
The frequency of arterial thromboembolic events was comparable between the two treatment arms in the phase 3 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. 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 frequency of gastrointestinal perforation was comparable between the treatment arms in the clinical study. However, based on the mechanism of action patients treated with Vargatef may have an increased risk of gastrointestinal perforations. 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.
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 LUME-Lung 1 trial. No dedicated studies 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.
Effect on QT interval
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.
Nintedanib exposure increased linearly with patient age, was inversely correlated to weight, and was generally higher in patients of Asian race. This may result in a higher risk of developing liver enzyme elevations. Close monitoring is recommended in patients with several of these risk factors.
In study 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.
4.5 Interaction with other medicinal products and other forms of interaction
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 side effects 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 with other medicinal products
Co-administration of nintedanib with docetaxel (75 mg/m²) did not alter the pharmacokinetics of either medicinal product to a relevant extent.
The potential for interactions of nintedanib with hormonal contraceptives was not explored.
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 being treated with Vargatef should be advised to avoid becoming pregnant while receiving this treatment and to use adequate contraception during and at least 3 months after the last dose of Vargatef. Since the effect of nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy.
There is no information on the use of Vargatef 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 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. 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 new-borns/infants 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.
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
Summary of the safety profile
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. 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.
Tabulated list of adverse reactions
Table 3 summarizes the frequencies of adverse drug reactions that were reported in the pivotal study LUME-Lung 1 for patients with NSCLC of adenocarcinoma tumour histology (n = 320). 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
Description of selected adverse reactions
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 enzyme elevations and hyperbilirubinaemia
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.
Neutropenia, febrile neutropenia and sepsis
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).
Although bleeding is an expected adverse reaction of nintedanib due to its mechanism of action, the bleeding incidence was comparable between the 2 treatment groups (placebo: 11.1 %, nintedanib: 10.9 %) in adenocarcinoma patients.
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 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
IRL – Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
The Medicines Authority
203 Level 3, Rue D'Argens
There is no specific antidote or treatment for nintedanib overdose. The highest single dose of nintedanib administered in phase I studies was 450 mg once daily. In addition, 2 patients had an overdose of maximum 600 mg twice daily (b.i.d.) up to eight days. Observed adverse events 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 case of overdose, treatment should be interrupted and general supportive measures initiated as appropriate.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors.
ATC code: not yet assigned.
Mechanism of action
Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and ß) and fibroblast growth factor receptors (FGFR 1-3) kinase activity. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling which is crucial for the proliferation and survival of endothelial as well as perivascular cells (pericytes and vascular smooth muscle cells). In addition Fms-like tyrosine-protein kinase (Flt)-3, lymphocyte-specific tyrosine-protein kinase (Lck) and proto-oncogene tyrosine-protein kinase Src (Src) are inhibited.
Tumour angiogenesis is an essential feature contributing to tumour growth, progression and metastasis formation and is predominantly triggered by the release of pro-angiogenic factors secreted by the tumour cell (i.e. VEGF and bFGF) to attract host endothelial as well as perivascular cells to facilitate oxygen and nutrient supply through the host vascular system. In preclinical disease models nintedanib, as single agent, effectively interfered with the formation and maintenance of the tumour vascular system resulting in tumour growth inhibition and tumour stasis. In particular, treatment of tumour xenografts with nintedanib led to a rapid reduction in tumour micro vessel density, pericytes vessel coverage and tumour perfusion.
Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) measurements showed an anti-angiogenic effect of nintedanib in humans. It was not clearly dose dependent, but most responses were seen at doses of ≥ 200 mg. Logistic regression revealed a statistically significant association of the anti-angiogenic effect to nintedanib exposure. DCE-MRI effects were seen 24 - 48 h after the first intake of the medicinal product and were preserved or even increased after continuous treatment over several weeks. No correlation of the DCE-MRI response and subsequent clinically significant reduction in target lesion size was found, but DCE-MRI response was associated with disease stabilization.
Clinical efficacy and safety
Efficacy in the pivotal phase 3 trial LUME-Lung 1
The efficacy and safety of Vargatef was investigated in 1314 adult patients with locally advanced, metastatic or recurrent NSCLC after one prior line of chemotherapy. `Locally recurrent´ was defined as local re-occurrence of the tumour without metastases at study entry. The trial included 658 patients (50.1 %) with adenocarcinoma, 555 patients (42.2 %) with squamous cell carcinoma, and 101 patients (7.7 %) with other tumour histologies.
Patients were randomized (1:1) to receive nintedanib 200 mg orally twice daily in combination with 75 mg/m2 of intravenous docetaxel every 21 days (n = 655) or placebo orally twice daily in combination with 75 mg/m2 of docetaxel every 21 days (n = 659). Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) status (0 versus 1), bevacizumab pretreatment (yes versus no), brain metastasis (yes versus no) and tumour histology (squamous versus non-squamous tumour histology).
Patient characteristics were balanced between treatment arms within the overall population and within subgroups according to histology. In the overall population, 72.7 % of the patients were male. The majority of patients were non-Asian (81.6 %), the median age was 60.0 years, the baseline ECOG performance status was 0 (28.6 %) or 1 (71.3 %); one patient had a baseline ECOG performance status of 2. Five point eight percent (5.8 %) of the patients had stable brain metastasis at study entry and 3.8 % had prior bevacizumab treatment.
The disease stage was determined at the time of diagnosis using Union Internationale Contre le Cancer (UICC) / American Joint Committee on Cancer (AJCC) Edition 6 or Edition 7. In the overall population, 16.0 % of the patients had disease stage < IIIB/IV, 22.4 %, had disease stage IIIB and 61.6 % had disease stage IV. 9.2 % of the patients entered the study with locally recurrent disease stage as had been evaluated at baseline. For patients with tumour of adenocarcinoma histology, 15.8 % had disease stage < IIIB/IV, 15.2 %, had disease stage IIIB and 69.0 % had disease stage IV.
5.8 % of the adenocarcinoma patients entered the study with locally recurrent disease stage as had been evaluated at baseline.
The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee (IRC) based on the intent-to-treat (ITT) population and tested by histology. Overall survival (OS) was the key secondary endpoint. Other efficacy outcomes included objective response, disease control, change in tumour size and health-related quality of life.
The addition of nintedanib to docetaxel led to a statistically significant reduction in the risk of progression or death by 21 % for the overall population (hazard ratio (HR) 0.79; 95% confidence interval (CI): 0.68 - 0.92; p = 0.0019) as determined by the Independent Review Committee. This result was confirmed in the follow-up PFS analysis (HR 0.85, 95% CI: 0.75 - 0.96; p = 0.0070) which included all events collected at the time of the final OS analysis. Overall survival analysis in the overall population did not reach statistical significance (HR 0.94; 95% CI: 0.83 - 1.05). Of note, pre-planned analyses according to histology showed statistically significant difference in OS between treatment arms in the adenocarcinoma population only (Table 4).
As shown in Table 4, the addition of nintedanib to docetaxel led to a statistically significant reduction in the risk of progression or death by 23 % for the adenocarcinoma population (HR 0.77; 95% CI: 0.62 - 0.96). In line with these observations, related study endpoints such as disease control and change in tumour size showed significant improvements.
Table 4: Efficacy results for study LUME-Lung 1 for patients with adenocarcinoma tumour histology
** Stratified by baseline ECOG PS (0 versus 1), brain metastases at baseline (yes versus no) and prior treatment with bevacizumab (yes v versus no).
*** OS analysis and follow-up PFS-analysis performed when 1121 death cases had been observed in the overall ITT population (535 events in adenocarcinoma patients).
+ Odds ratio and p-value were obtained from a logistic regression model adjusted for baseline ECOG Performance Score (0 versus 1).
° Adjusted mean of best-% change from baseline and p-value generated from an ANOVA model adjusting for baseline ECOG PS (0 versus 1), brain metastases at baseline (yes versus no) and prior treatment with bevacizumab (yes versus no).
A statistically significant improvement in OS favouring treatment with nintedanib plus docetaxel was demonstrated in patients with adenocarcinoma with a 17 % reduction in the risk of death (HR 0.83, p = 0.0359) and a median OS improvement of 2.3 months (10.3 versus 12.6 months, Figure 1).
Figure 1: Kaplan-Meier curve for overall survival for patients with adenocarcinoma tumour histology by treatment group in trial LUME-Lung 1
尼达尼布软胶囊|Vargatef（nintedanib soft capsules）
简介： 英文药名：Vargatef（nintedanib soft capsules） 中文药名：尼达尼布软胶囊 生产厂家：勃林格殷格翰（Boehringer Ingelheim）药品介绍2014年11月28日，欧盟委员会（EC）已批准nintedanib联合多西紫杉 ...