Nintedanib

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.

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 C_max upon co-administration with rifampicin compared to administration of nintedanib alone.

Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decrease exposure to nintedanib. Selection of an alternate concomitant medicinal product with no or minimal P-gp induction potential should be 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 C_max in a dedicated drug-drug interaction study.

If co-administered with nintedanib, potent P-gp inhibitors (e.g. ketoconazole, erythromycin or cyclosporine) 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.

Chronic fibrosing interstitial lung diseases

In adult patients with mild hepatic impairment (Child Pugh A), the recommended dose of Ofev is 100 mg twice daily approximately 12 hours apart. In patients with mild hepatic impairment (Child Pugh A), treatment interruption or discontinuation for management of adverse reactions should be considered.

Locally advanced, metastatic or locally recurrent non-small cell lung cancer

Nintedanib is predominantly eliminated via biliary/faecal excretion (>90%). Exposure increased in patients with hepatic impairment. No adjustment of the starting dose is needed for patients with mild hepatic impairment (Child Pugh A) based on clinical data.

The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (<30 mL/min creatinine clearance).

The safety and efficacy of nintedanib have not been investigated in patients with hepatic impairment classified as Child Pugh B and C. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Ofev is not recommended.

In a dedicated pharmacokinetic study, concomitant treatment of nintedanib with pirfenidone was investigated in patients with IPF. Based on these results, there is no evidence of a relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when administered in combination. Given the similarity in safety profiles for both medicinal products, additive adverse reactions, including gastrointestinal and hepatic adverse events, may be expected. The benefit-risk balance of concomitant treatment with pirfenidone has not been established.

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. Nintedanib should only be initiated at least 4 weeks after abdominal surgery.

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 nintedanib should therefore only be initiated or – in case of perioperative interruption – resumed based on clinical judgement of adequate wound healing.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating nintedanib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

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 nintedanib. 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 nintedanib 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.

Chronic fibrosing interstitial lung diseases

Data on the use of nintedanib in patients with pulmonary hypertension is limited. Patients with significant pulmonary hypertension (cardiac index ≤2 L/min/m², or parenteral epoprostenol/treprostinil, or significant right heart failure) were excluded from the INBUILD and SENSCIS trials.

Nintedanib should not be used in patients with severe pulmonary hypertension. Close monitoring is recommended in patients with mild to moderate pulmonary hypertension.

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.

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 nintedanib 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 nintedanib.

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.

Women of childbearing potential / Contraception

Nintedanib may cause foetal harm in humans. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with nintedanib and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of nintedanib. Nintedanib does not relevantly affect the plasma exposure of ethinylestradiol and levonorgestrel. 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.

Fertility

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.

Chronic fibrosing interstitial lung diseases

Summary of the safety profile

In clinical trials and during the post-marketing experience, 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.

Tabulated list of adverse reactions

Table 1 provides a summary of the adverse drug reactions (ADRs) by MedDRA System Organ Class (SOC) and frequency category 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).

Table 1. Summary of ADRs per frequency category:

Description of selected adverse reactions

Diarrhoea

In clinical trials, diarrhoea was the most frequent gastro-intestinal event reported. In most patients, the event was of mild to moderate intensity. More than two thirds of patients experiencing diarrhoea reported its first onset already during the first three months of treatment. In most patients, the events were managed by anti-diarrhoeal therapy, dose reduction or treatment interruption. An overview of the reported diarrhoea events in the clinical trials is listed in Table 2:

Table 2. Diarrhoea in clinical trials over 52 weeks:

Hepatic enzyme increased

In the INPULSIS trials, liver enzyme elevations were reported in 13.6% versus 2.6% of patients treated with nintedanib and placebo, respectively. In the INBUILD trial, liver enzyme elevations were reported in 22.6% versus 5.7% of patients treated with Nintedanib and placebo, respectively. In the SENSCIS trial, liver enzyme elevations were reported in 13.2% versus 3.1% of patients treated with nintedanib and placebo, respectively. Elevations of liver enzymes were reversible and not associated with clinically manifest liver disease.

Bleeding

In clinical trials, the frequency of patients who experienced bleeding was slightly higher in patients treated with nintedanib or comparable between the treatment arms (nintedanib 10.3% versus placebo 7.8% for INPULSIS; nintedanib 11.1% versus placebo 12.7% for INBUILD; nintedanib 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 (nintedanib 1.3% versus placebo 1.4% for INPULSIS; nintedanib 0.9% versus placebo 1.5% for INBUILD; nintedanib 1.4% versus placebo 0.7% for SENSCIS).

Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous organ systems, with the most frequent being gastrointestinal.

Proteinuria

In clinical trials, the frequency of patients who experienced proteinuria was low and comparable between the treatment arms (nintedanib 0.8% versus placebo 0.5% for INPULSIS; nintedanib 1.5% versus placebo 1.8% for INBUILD; nintedanib 1.0% versus placebo 0.0% for SENSCIS). Nephrotic syndrome has not been reported in clinical trials. Very few cases of nephrotic range proteinuria with or without renal function impairment have been reported post-marketing. Histological findings in individual cases were consistent with glomerular microangiopathy with or without renal thrombi. Reversal of the symptoms has been observed after nintedanib was discontinued, with residual proteinuria in some cases. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.

Paediatric population

There are limited safety data for nintedanib in pediatric patients.

A total of 39 patients aged 6 to 17 years were treated in a randomised, double-blind, placebo-controlled trial of 24 weeks duration, followed by open label treatment with nintedanib of variable duration. Consistent with the safety profile seen in adult patients with IPF, other chronic fibrosing ILDs with progressive phenotype and SSc-ILD, the most frequently reported adverse reactions with nintedanib during placebo-controlled period were diarrhoea (38.5%), vomiting (26.9%), nausea (19.2%), abdominal pain (19.2%), and headache (11.5%).

Hepatobiliary disorders reported with nintedanib during placebo-controlled period were liver injury (3.8%) and increased liver function test (3.8%). Due to limited data, it is uncertain if the risk for drug-induced liver injury is similar in children as compared to adults.

Based on preclinical findings, bone, growth and teeth development were monitored as potential risks in the paediatric clinical trial. The potential impact on growth and tooth development is unknown.

Long term safety data in paediatric patients are not available. There are uncertainties on the potential impact on growth, tooth development, puberty, and the risk of liver injury.

Locally advanced, metastatic or locally recurrent non-small cell lung cancer

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 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). 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.

Table 3. Summary of ADRs per frequency category:

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.

Description of selected adverse reactions

Diarrhoea

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 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.

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.

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. Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous system organs, with the most frequent being respiratory.

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. Peripheral neuropathy was reported in 16.5% of patients in the placebo arm and in 19.1% of patients in the nintedanib arm.