Summary of the risk management plan (RMP) for Vargatef (nintedanib)

Transcription

1 EMA/606748/2014 Summary of the risk management plan (RMP) for Vargatef (nintedanib) This is a summary of the risk management plan (RMP) for Vargatef, which details the measures to be taken in order to ensure that Vargatef is used as safely as possible. For more information on RMP summaries, see here. This RMP summary should be read in conjunction with the EPAR summary and the product information for Vargatef, which can be found on Vargatef s EPAR page. Overview of disease epidemiology Vargatef is a cancer medicine used to treat adults with a type of lung cancer known as non-small cell lung cancer. Lung cancer is the most common cancer worldwide. It is the leading cause of cancer deaths in men and the second leading cause of cancer deaths in women. In 2012, there were about 410,000 newly diagnosed lung cancer cases in Europe. Non-small cell lung cancer accounts for approximately 85% of lung cancer cases. At diagnosis, 10-15% of patients have locally advanced cancer (stage IIIB), and 40% of patients have metastatic cancer (stage IV, when the cancer has spread to other parts of the body). Summary of treatment benefits Vargatef is used to treat a type of non-small cell lung cancer called adenocarcinoma, when the cancer is locally advanced, metastatic or locally recurrent (when the cancer has come back in the same area). It contains the active substance nintedanib. Vargatef is used in combination with another cancer medicine called docetaxel in patients who have already received previous treatment with chemotherapy medicines. In a main study (study ) involving 1,314 patients with advanced or recurrent non-small cell lung cancer that did not respond to a previous treatment, Vargatef taken in combination with docetaxel was shown to be more effective than docetaxel alone at delaying progression of the cancer. Progression-free survival (the time patients lived without their disease getting worse) was 3.5 months in patients receiving Vargatef plus docetaxel, compared with 2.7 months in patients receiving docetaxel alone. In addition, Vargatef led to an improvement in overall survival (how long patients lived) in the subgroup of patients with non-small cell lung cancer of the adenocarcinoma type: overall survival was 12.6 months in patients treated with Vargatef plus docetaxel, compared with 10.3 months in patients treated with docetaxel alone. Page 1/7

2 Unknowns relating to treatment benefits The main study and the supporting study included mainly adult Caucasians aged below 65 years; there are no data to suggest that the effectiveness of Vargatef would be different across other patient subpopulations defined by age, gender, race or geographical region. Summary of safety concerns Important identified risks Risk Preventability Diarrhoea Liver enzyme elevations and abnormally high bilirubin blood levels (hyperbilirubinaemia) Abnormally low level of a type of white blood cell (neutropenia) In the main study with Vargatef plus docetaxel (study ), diarrhoea was very common in patients on Vargatef (occurring in around 4 patients in 10). The majority of diarrhoea events were of mild to moderate severity, and manageable by lowering the dose of Vargatef and using medicines for diarrhoea, such as loperamide. In study , increased levels of liver enzymes in the blood were very common in patients treated with Vargatef and docetaxel (seen in around 4 patients in 10), and occurred more often in these patients than in those treated with placebo and docetaxel. Increases in bilirubin were also seen in up to 1 patient in 10. Most increases were of mild or moderate severity, returned to normal in the majority of patients, and did not lead to apparent liver disease. In study more than 1 patient in 10 treated with Vargatef and docetaxel had neutropenia with or without fever, which was more than those treated with placebo and docetaxel. Neutropenia is a known side effect of docetaxel. Patients who develop diarrhoea should immediately contact their doctor. Management should start at the first signs of diarrhoea. This includes adequate intake of fluids and electrolytes (to prevent or treat dehydration) and use of diarrhoea medicines. For patients with severe diarrhoea doctors may need to consider stopping or lowering the dose of Vargatef. Recommended dose reductions for Vargatef are provided in the summary of product characteristics (SmPC). Liver enzymes and bilirubin levels should be investigated before starting treatment with Vargatef plus docetaxel and should be closely and periodically monitored during treatment. If relevant liver enzyme elevations are measured, interruption of treatment followed by the use of lower doses or complete cessation of Vargatef treatment should be considered. Recommended dose reductions for Vargatef are provided in the SmPC. Blood counts should be checked during therapy, in particular during the combination treatment with docetaxel. Recommended dose reductions for Vargatef are provided in the SmPC. Patients who develop fever should immediately contact their doctor as this could be a symptom of febrile neutropenia. Page 2/7

3 Risk Preventability Bacterial infection in the bloodstream (sepsis) Formation of blood clots in the veins (venous thromboembolism or VTE) Organ perforation (gastrointestinal and nongastrointestinal) Bleeding High blood pressure (hypertension) In study patients treated with Vargatef and docetaxel had more sepsis (around 1 patient in 100) than those treated with placebo and docetaxel. Sepsis may be a complication of neutropenia and is a known side effect of docetaxel. In study , patients on Vargatef and docetaxel experienced more VTE, in particular deep vein thrombosis, compared with patients on placebo and docetaxel. VTE may occur between 1 and 10 patients in 100. In study patients treated with Vargatef and docetaxel did not have more organ perforations when compared with patients treated with placebo and docetaxel. Few patients experienced a gastrointestinal (affecting the gut) or nongastrointestinal perforation. In study , the number of patients with adenocarcinoma who experienced bleeding was comparable between the treatment arms. In patients with squamous cell carcinoma, more patients receiving Vargatef experienced bleeding than patients on placebo. High blood pressure is a known side effect of medicines like Vargatef that belong to a group known as VEGFR Blood counts should be checked during therapy, in particular during the combination treatment with docetaxel. Recommended dose reductions for Vargatef are provided in the SmPC. Patients who develop fever should immediately contact their doctor as this could be a symptom of sepsis. Patients should be closely monitored for VTE. Vargatef should be stopped in patients with life-threatening VTE reactions. Patients who have had abdominal surgery in the past should be treated with particular caution. Vargatef should be started at least 4 weeks after major surgery. Vargatef should be permanently stopped in patients who develop gastrointestinal perforation. Patients taking anticoagulants (blood thinners), such as warfarin or phenprocoumon, should be checked regularly for changes in measures of blood clotting (e.g. prothrombin time, INR) or clinical bleeding episodes. Patients who have any major bleeding should contact their doctor immediately. Patients with brain metastases should be closely watched for signs and symptoms of bleeding in the brain. Treatment with Vargatef is not recommended in patients with recent lung bleeding (>2.5 ml of red blood) and those with certain centrally located tumours (i.e. with radiographic evidence of local invasion of major blood vessels or of cavitary or necrotic tumours). Patients taking medicines for high blood pressure should have their blood pressure measured at regular intervals Page 3/7

4 Risk Preventability inhibitors. In study , the number of patients who experienced high blood pressure was increased in the Vargatef arm compared with the placebo arm, but high blood pressure occurred less frequently with Vargatef (in around 3 patients in 100) than it is known to occur with other VEGFR inhibitors. Most blood pressure elevations were of mild or moderate severity and resolved in the majority of patients. The number of patients who started a new treatment for high blood pressure during study was low in the Vargatef arm. as indicated by their hypertensive disease. All patients should have routine blood pressure measurements as clinically indicated. Important potential risks Risk Blood clots in the arteries (arterial thromboembolism, ATE) Treatment in pregnant women and harmful effect on the unborn child (teratogenicity) Liver dysfunction Heart problems (cardiac failure) Alteration of the electrical activity of ATE is a known effect of treatment with medicines belonging to the class known as VEGFR inhibitors. There is no evidence of an increased frequency of ATE in non-small cell lung cancer patients based on data collected in study However, in patients suffering from another lung condition, idiopathic pulmonary fibrosis (IPF), ATE occurred more frequently in patients treated with Vargatef than in those who received placebo, so it is considered a possible risk. Vargatef has not been investigated in pregnant women. The properties of Vargatef suggest a potential adverse effect on the embryo/fetus that was confirmed in a study in animals. Therefore, as a precaution, women should not be treated with Vargatef during pregnancy unless the clinical condition requires treatment. Women who can become pregnant should be advised to use adequate contraception during and at least 3 months after the last dose of the medicine. As mentioned above, increases of liver enzyme values and bilirubin have been observed in patients treated with Vargatef. Liver enzyme increases in clinical studies with Vargatef mostly returned to normal when Vargatef treatment was interrupted. However, it cannot be excluded that certain patients may develop liver problems (hepatic failure). Some medicines belonging to the same class as Vargatef may cause heart problems such as heart failure or congestive heart failure. In study , very few patients experienced cardiac failure in both the placebo and the Vargatef study arms. Heart failure was not reported in patients with adenocarcinoma. Alteration of the electrical activity of the heart (so-called QT prolongation) has been observed with some medicines belonging to the same class as Vargatef Page 4/7

5 Risk the heart (QT prolongation) so it is considered a potential risk. There is no evidence at present that Vargatef increases the risk for QT prolongation, based on studies in animals, a dedicated study in patients with renal cell cancer and study in patients with non-small cell lung cancer. Missing information Risk Treatment in breastfeeding women Treatment in patients with liver impairment Vargatef has not been investigated in breastfeeding women. Pre-clinical studies showed that small amounts of the active substance nintedanib and its metabolites pass into the milk of lactating rats. Therefore, as a precaution, breastfeeding should be discontinued during treatment with Vargatef. Most patients in the clinical trial programme in oncology had normal liver function (81.5%) or mildly reduced liver function (14.9%). Patients with signs of more severe liver impairment (i.e. total bilirubin above the upper limit of normal (ULN), and/or alanine aminotransferase (ALT) above 1.5x ULN, and/or aspartate aminotransferase (AST) above 1.5x ULN) were excluded from study There are insufficient data to evaluate whether there is a risk from Vargatef treatment in patients with moderate or severe liver impairment. Three phase I/II studies examined patients with liver impairment (studies , , and , which included patients with advanced hepatocellular carcinoma). The adverse event profile for these patients was comparable with that of the overall population of cancer patients exposed to Vargatef. Treatment in patients with kidney impairment Treatment in patients with healing wounds subpopulations with conditions affecting the central nervous system such as dementia, depression and brain metastasis, or with conditions Patients with reduced kidney function (serum creatinine more than 1.5 times the normal limit) were excluded from the main study in non-small cell lung cancer patients treated with Vargatef plus docetaxel. There are insufficient data to evaluate whether there is a risk from Vargatef treatment in patients with kidney impairment. Due to its mode of action, Vargatef may impair wound healing. Therefore, patients who had major injuries and/or surgery within the 10 days prior to trial randomisation, with incomplete wound healing, were excluded from study During the study, 25 patients in the placebo arm and 19 patients in the Vargatef arm had surgery; wound healing was not identified as a safety concern. Nevertheless, further data are needed from post-marketing experience to fully exclude this potential safety issue. There is limited information on the safety of Vargatef in patients with central nervous system conditions such as dementia, depression and brain metastasis, or other conditions such as arthritis and osteoporosis. Page 5/7

6 Risk such as arthritis and osteoporosis patients weighing less than 50 kg Interaction with proteins called organic anion transporters (OAT1 and OAT3) In study , there was a higher frequency of side effects in patients weighing less than 50 kg treated with Vargatef plus docetaxel compared with patients weighing 50 kg or more. However, the number of patients with a body weight less than 50 kg was small and therefore insufficient to evaluate whether there is a risk from Vargatef treatment in this population. Laboratory investigations are currently ongoing to evaluate whether the active substance nintedanib might block some proteins called OAT1 and OAT3 that are responsible for the transport of substances in the kidney. Summary of risk minimisation measures by safety concern All medicines have a summary of product characteristics (SmPC) which provides physicians, pharmacists and other healthcare professionals with details on how to use the medicine, and also describes the risks and recommendations for minimising them. Information for patients is available in lay language in the package leaflet. The measures listed in these documents are known as routine risk minimisation measures. The SmPC and the package leaflet are part of the medicine s product information. The product information for Vargatef can be found on Vargatef s EPAR page. This medicine has no additional risk minimisation measures. Planned post-authorisation development plan Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results : A multicentre, open label, phase I/randomised phase II study to evaluate safety, pharmacokinetics and efficacy of BIBF 1120 in comparison with sorafenib for advanced hepatocellular carcinoma patients Phase I: maximum tolerated dose (MTD) in patients with mild and moderate liver impairment and recommended dose for phase II Phase II: efficacy and safety of nintedanib as compared with sorafenib in patients carcinoma patients with hepatic impairment Started Q Page 6/7

7 : A multicenter, open label, phase I/randomized phase II study to evaluate safety, pharmacokinetics and efficacy of BIBF 1120 in comparison with sorafenib for advanced hepatocellular carcinoma patients in Asia Phase I: MTD in patients with mild and moderate liver impairment and recommended dose for phase II Phase II: efficacy and safety of nintedanib as compared with sorafenib in patients carcinoma patients with hepatic impairment Started Q : An open label, dose escalation phase I study to evaluate the safety and tolerability of continuous twicedaily oral treatment of nintedanib in Japanese patients carcinoma To evaluate MTD in Japanese patients carcinoma and to recommend dose of nintedanib for further trials in two groups of patients according to liver function To evaluate the pharmacokinetic (PK) of nintedanib and to explore a correlation of PK with degree of liver impairment Japanese patients with hepatic impairment Started Q PK1407T: In vitro evaluation of the interaction of nintedanib with human OAT transporters To determine the interaction potential of nintedanib toward OAT1 and OAT3 In vitro inhibitory potential on OAT1 and OAT3 Started End of 2014 Studies which are a condition of the marketing authorisation None of the above listed studies is a condition of the marketing authorisation. Summary of changes to the risk management plan over time Not applicable. This summary was last updated in Page 7/7