Chemical formula: C₃₁H₃₃N₅O₄ Molecular mass: 539.625 g/mol PubChem compound: 9809715
Nintedanib interacts in the following cases:
No QT prolongation was observed for nintedanib in the clinical trial program. 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.
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.
Nintedanib is a substrate of P-gp. 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 nintedanib.
Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A). 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.
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, gammaglutamyltransferase (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 nintedanib 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 nintedanib is continued as monotherapy after discontinuation of docetaxel.
If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with nintedanib may be required. 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 nintedanib should be interrupted. Unless there is an alternative cause established, nintedanib should be permanently discontinued.
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. Close monitoring is recommended in patients with these risk factors.
VEGFR inhibition might be associated with an increased risk of bleeding. In the clinical trial (LUME-Lung 1) with nintedanib, the frequency of bleeding in both treatment arms was comparable. 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 nintedanib.
Non-serious and serious bleeding events, some of which were fatal, have been reported in the postmarketing 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. Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous system organs, with the most frequent being respiratory.
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 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 nintedanib should therefore only be initiated or – in case of perioperative interruption – resumed based on clinical judgement of adequate wound healing.
Administration of nintedanib may increase blood pressure. Systemic blood pressure should be measured periodically and as clinically indicated.
In case of specific elevations of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) values to >3 x upper limit normal (ULN) in conjunction with an increase of total bilirubin to ≥2 x ULN and alkaline phosphatase (ALKP) <2 x ULN (see table) treatment with nintedanib should be interrupted. Unless there is an alternative cause established, nintedanib should be permanently discontinued.
Recommended dose adjustments for nintedanib in case of AST and/or ALT and bilirubin elevations:
| AST / ALT and bilirubin elevations | Dose adjustment |
|---|---|
| Elevation of AST and/or ALT values to >2.5 x ULN in conjunction with total bilirubin elevation to ≥1.5 x ULN OR Elevation of AST and/or ALT values to >5 x ULN | After treatment interruption and recovery of transaminase-values to ≤2.5 x 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 x ULN in conjunction with an increase of total bilirubin to ≥2 x ULN and ALKP <2 x ULN | Unless there is an alternative cause established, nintedanib should be permanently discontinued |
AST: Aspartate aminotransferase; ALT: Alanine aminotransferase
ALKP: Alkaline phosphatase; ULN: Upper limit normal
Diarrhoea was the most frequently reported gastro-intestinal adverse reaction and appeared in close temporal relationship with the administration of docetaxel. In the clinical trial LUME-Lung 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 nintedanib.
Nausea and vomiting, mostly of mild to moderate severity, were frequently reported gastrointestinal adverse reactions. Interruption, dose reduction or discontinuation of therapy with nintedanib 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 nintedanib may be required.
As initial measure for the management of adverse reactions 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. Dose adjustments in 100 mg steps per day (i.e. a 50 mg reduction per dosing) based on individual safety and tolerability are recommended as described in the following table.
Recommended dose adjustments for 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 2 nd dose reduction is considered necessary – from 150 mg twice daily to 100 mg twice daily. |
| Vomiting ≥ grade 2 AND/OR Nausea ≥ grade 3 despite anti-emetic treatment | |
| Other non-haematological or haematological adverse reaction of ≥ grade 3 |
* CTCAE: Common Terminology Criteria for Adverse Events
Patients treated with nintedanib 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. Nintedanib should be discontinued in patients with life-threatening venous thromboembolic reactions.
There is no information on the use of nintedanib in pregnant women, but preclinical studies in animals have shown reproductive toxicity of this active substance. 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 nintedanib. Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy with nintedanib.
If the patient becomes pregnant while receiving nintedanib, she should be apprised of the potential hazard to the foetus. Termination of the treatment with nintedanib 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 nintedanib.
Nintedanib may cause foetal harm in humans. Women of childbearing potential being treated with nintedanib 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 nintedanib. 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.
Based on preclinical investigations there is no evidence for impairment of male fertility. There are no human or animal data on potential effects of nintedanib on female fertility available.
Nintedanib 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 nintedanib.
Nintedanib has been studied in clinical trials of 1,529 patients suffering from IPF. The safety data provided in the following are based on the two Phase III, randomised, double-blind, placebo-controlled studies in 1,061 patients comparing treatment with nintedanib 150 mg twice daily to placebo for 52 weeks (INPULSIS-1 and INPULSIS-2) and based on data observed during the post-marketing period.
The most frequently reported adverse reactions associated with the use of nintedanib included diarrhoea, nausea and vomiting, abdominal pain, decreased appetite, weight decreased and hepatic enzyme increased.
The below list provides a summary of the adverse reactions by MedDRA System Organ Class (SOC) and frequency category.
It summarizes the frequencies of adverse drug reactions (ADRs) that were reported in the nintedanib group (638 patients) pooled from the two placebo-controlled Phase III clinical trials of 52 weeks duration or from the post-marketing period.
Frequency categories are defined using the following convention: 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 decreasing seriousness.
Uncommon: Thrombocytopenia
Common: Weight decreased, Decreased appetite
Uncommon: Dehydration
Uncommon: Myocardial infarction
Common: Bleeding
Uncommon: Hypertension
Not known: Aneurysms and artery dissections
Very common: Diarrhoea, Nausea, Abdominal pain
Common: Vomiting
Uncommon: Pancreatitis, Colitis
Very common: Hepatic enzyme increased
Common: Alanine aminotransferase (ALT) increased, Aspartate aminotransferase (AST) increased, Gamma glutamyl transferase (GGT) increased
Uncommon: Drug induced liver injury, Hyperbilirubinaemia, Blood alkaline phosphatase (ALKP) increased
Common: Rash
Uncommon: Pruritus, Alopecia
Not known: Renal failure
Common: Headache
Diarrhoea was reported in 62.4% of patients treated with nintedanib. The event was reported to be of severe intensity in 3.3% of nintedanib treated patients. More than two thirds of patients experiencing diarrhoea reported its first onset already during the first three months of treatment. Diarrhoea led to permanent treatment discontinuation in 4.4% of patients; otherwise the events were managed by anti-diarrhoeal therapy, dose reduction or treatment interruption.
Liver enzyme elevations were reported in 13.6% of nintedanib treated patients. Elevations of liver enzymes were reversible and not associated with clinically manifest liver disease.
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. The below list provides a summary of the adverse reactions by System Organ Class (SOC). Information about selected adverse reactions observed from the LUME-Lung 1 trial are described below.
The list 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.
Common: Febrile neutropenia, Abscesses, Sepsis
Very common: Neutropenia (includes febrile neutropenia)
Common: Thrombocytopenia
Very common: Decreased appetite, Electrolyte imbalance
Common: Dehydration, Weight decreased
Very common: Peripheral neuropathy
Common: Headache1
Uncommon: Myocardial infarction
Very common: Bleeding1
Common: Venous thromboembolism3, Hypertension
Not known: Aneurysms and artery dissections
Very common: Diarrhoea, Vomiting, Nausea, Abdominal pain
Uncommon: Perforation1, Pancreatitis2
Not known: Colitis
Very common: Alanine aminotransferase (ALT) increased, Aspartate aminotransferase (AST) increased, Blood alkaline phosphatase (ALKP) increased
Common: Hyperbilirubinaemia, Gammaglutamyltransferase (GGT) increased
Uncommon: Drug-induced liver injury
Very common: Mucositis (including stomatitis), Rash, Alopecia1
Common: Pruritus
Uncommon: Renal failure
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.
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.
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.
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.
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.
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