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Vargatef is a brand name for Nintedanib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Vargatef is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy.
Verbatim from this product's EMA label. Tap a section to expand.
Treatment with Vargatef should be initiated and supervised by a physician experienced in the use of anticancer therapies. Posology The recommended dose of nintedanib is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21 day docetaxel treatment cycle.
Vargatef must not be taken on the same day of docetaxel chemotherapy administration (= day 1). If a dose of nintedanib is missed, administration should resume at the next scheduled time at the recommended dose. The individual daily doses of nintedanib should not be increased beyond the recommended dose to make up for missed doses.
The recommended maximum daily dose of 400 mg should not be exceeded. 3 Patients may continue therapy with nintedanib after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs.
For posology, methods of administration, and dose modifications of docetaxel, please refer to the corresponding product information for docetaxel. Dose adjustments As initial measure for the management of adverse reactions (see Tables 1 and 2) treatment with nintedanib should be temporarily interrupted until the specific adverse reaction has resolved to levels that allow continuation of therapy (to grade 1 or baseline).
Nintedanib treatment may be resumed at a reduced dose. e. a 50 mg reduction per dosing) based on individual safety and tolerability are recommended as described in Table 1 and Table 2. e. if a patient does not tolerate 100 mg twice daily, treatment with Vargatef should be permanently discontinued.
In case of specific elevations of aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) values to > 3 × upper limit normal (ULN) in conjunction with an increase of total bilirubin to ≥ 2 × ULN and alkaline phosphatase (ALKP) < 2 × ULN (see Table 2) treatment with Vargatef should be interrupted.
4).
Table 1:
Recommended dose adjustments for Vargatef (nintedanib) in case of diarrhoea, vomiting and other non-haematological or haematological adverse reactions CTCAE* Adverse reaction Dose adjustment Diarrhoea ≥ grade 2 for more than 7 consecutive days despite anti-diarrhoeal treatment OR Diarrhoea ≥ grade 3 despite anti-diarrhoeal treatment After treatment interruption and recovery to grade 1 or baseline, dose reduction from 200 mg twice daily to 150 mg twice daily and – if a 2nd dose reduction is considered necessary – from 150 mg twice daily to 100 mg twice daily.
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).
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 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. 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.
3%) of adenocarcinoma patients in the nintedanib arm. The 11 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.
8). 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. 2). 8). 2) may be required despite appropriate supportive care.
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 5 electrolytes should be monitored, if relevant gastrointestinal adverse events occur.
2). 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 (including fatal cases).
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.
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).
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.
1.
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5 × ULN in conjunction with bilirubin to normal, dose reduction from 200 mg twice daily to 150 mg twice daily and – if a 2nd dose reduction is considered necessary – from 150 mg twice daily to 100 mg twice daily. Elevation of AST and/or ALT values to > 3 × ULN in conjunction with an increase of total bilirubin to ≥ 2 × ULN and ALKP < 2 × ULN Unless there is an alternative cause established, Vargatef should be permanently discontinued AST: Aspartate aminotransferase; ALT: Alanine aminotransferase ALKP: Alkaline phosphatase; ULN: Upper limit normal 4 Special populations Paediatric population The safety and efficacy of Vargatef in children aged 0-18 years have not been established.
Elderly patients (≥ 65 years) No overall differences in safety and efficacy were observed for elderly patients. 1). 2). 2). Safety data for Black and African American patients are limited. 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). Hepatic impairment Nintedanib is predominantly eliminated via biliary/faecal excretion (> 90%).
2). No adjustment of the starting dose is needed for patients with mild hepatic impairment (Child Pugh A) based on clinical data. Limited safety data available from 9 patients with moderate hepatic impairment (Child Pugh B) are insufficient to characterize this population.
The safety, efficacy and pharmacokinetics of nintedanib have not been investigated in patients with severe hepatic impairment (Child Pugh C). 2). Method of administration Vargatef capsules must be taken orally, preferably with food, swallowed whole with water, and must not be chewed.
6).
2, respectively. 8% of nintedanib-treated patients. Approximately one third of these patients had liver-related adverse reactions of ≥ grade 3 severity. 2% of patients. In the majority of patients, elevations of liver parameters were reversible.
2, respectively. Neutropenia, febrile neutropenia and sepsis Sepsis and febrile neutropenia have been reported as subsequent complications of neutropenia. 5%) were increased under treatment with nintedanib as compared to the placebo arm.
4). Bleeding 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.
4). Perforation 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 Peripheral neuropathy is also known to occur with docetaxel treatment.
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 the national reporting system listed in Appendix V.
Transaminase, ALKP and bilirubin levels should be investigated before initiation of the combination treatment with Vargatef plus docetaxel. 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.
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 × ULN; total bilirubin ≥ 2 × ULN and ALKP < 2 × ULN) treatment with Vargatef should be interrupted.
2). Patients with low body weight (< 65 kg), Asian and female patients have a higher risk of elevations in liver enzymes. 2). Close monitoring is recommended in patients with these risk factors. 8). Patients should be monitored during nintedanib therapy, with particular attention to those patients exhibiting risk factors for renal impairment/failure.
2 Dose adjustments). 6 Haemorrhage VEGFR inhibition might be associated with an increased risk of bleeding. 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. 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 […]