Summary of the risk management plan (RMP) for Zykadia (ceritinib)

Transcription

1 EMA/154751/2015 Summary of the risk management plan (RMP) for Zykadia (ceritinib) This is a summary of the risk management plan (RMP) for Zykadia, which details the measures to be taken in order to ensure that Zykadia 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 Zykadia, which can be found on Zykadia s EPAR page. Overview of disease epidemiology Zykadia is a cancer medicine used to treat adults with a type of lung cancer known as non-small cell lung cancer (NSCLC) when the disease is, which means that the cancer cells have abnormal changes in the gene responsible for producing a protein called ALK (anaplastic lymphoma kinase), resulting in stimulation of the growth of the cancer cells. 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. NSCLC 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). Patients with NSCLC are more likely to be younger, never to have smoked and to be diagnosed at an advanced stage of cancer. Their average survival without specific therapy for tumors is reported to be just over 12 months (median overall survival 12.2 months). Summary of treatment benefits Zykadia contains the active substance ceritinib. It is used to treat NSCLC when the disease is advanced and has already been treated before with another cancer medicine called crizotinib (Xalkori). Zykadia has been investigated in two main studies involving 303 patients in whom the disease progressed despite previous treatment with crizotinib. In both studies, which were still ongoing at the time of Zykadia s evaluation, the medicine was not compared with any other treatment. Response to treatment was assessed using body scans and standardised criteria used for solid tumours, with complete response being when the patient had no remaining signs of the cancer. In one study 56% of patients given Zykadia (92 of 163) were considered by the treating doctors to have shown a complete or partial response to the medicine at the time of analysis. The average length of response was 8.3 months. In the second study, the overall response rate at the time of analysis was 37% (52 of 140 patients) and the average length of response was 9.2 months. Page 1/7

2 Unknowns relating to treatment benefits In the studies used to support approval of Zykadia, most patients were younger than 65 years old and Caucasian or Asian. The benefits in adults are expected to be the same regardless of age, race, or gender. There is no information on the use of the medicine in children. Summary of safety concerns Important identified risks Risk What is known Preventability Liver damage (hepatotoxicity) Changes in the electrical activity of the heart (QT prolongation) Inflammation of the lungs (ILD/ pneumonitis) High blood sugar levels (hyperglycaemi a) Zykadia very commonly causes abnormal results of liver laboratory tests, affecting more than 1 patient in 10. These are not usually associated with noticeable symptoms, but increases may be a warning of possible harm to the liver. In less than 1 patient in 100 the medicine can cause injury to the liver, which may be severe. In studies, changes of concern in the electrical activity of the heart were commonly reported with Zykadia and may affect more than 6 patients in 100. Inflammation of the lungs is a common complication in patients treated with Zykadia and may affect more than 3 patients in 100. Cases mostly improved or resolved after interrupting treatment, but during studies, two patients died due to inflammation of the lungs. High blood sugar has been reported commonly in patients treated with Zykadia, affecting about 8 patients in 100. The risk of high blood sugar levels is higher in patients who had a history of Liver tests should be carried out before starting Zykadia, every two weeks for the first month and monthly thereafter. The product information contains guidance for doctors on when treatment should be interrupted and restarted at a lower dose or stopped altogether. Zykadia should not be used in patients with an inherited condition known as long QT syndrome. Heart rate and rhythm should be checked periodically using ECG (a test of the electrical activity of the heart) and the level of certain minerals in the blood should be monitored, especially in patients with slow or abnormal heart rate, heart failure, and in patients who are also taking medications that are known to cause any changes in the electrical activity of the heart. The product information contains guidance for doctors on when treatment should be interrupted and restarted at a lower dose or stopped altogether. Patients should be monitored for lung symptoms that indicate inflammation. Zykadia should be stopped in patients who develop lung inflammation due to treatment. Blood sugar levels should be checked before starting Zykadia and monitored regularly during treatment. Medicines to manage high blood sugar may be prescribed by the doctor as appropriate. Page 2/7

3 Risk What is known Preventability Nausea (feeling sick), vomiting and diarrhoea (GI toxicity) Slow heart rate (bradycardia) diabetes or were taking corticosteroids, medicines known to raise sugar in the blood. Symptoms affecting the gut such as nausea, vomiting, and diarrhoea are very common, affecting up to 8 patients in 10 treated with Zykadia; although often mild, more severe symptoms have been reported in more than 1 patient in 10. Slow heart rate has been noted in patients treated with Zykadia, affecting more than 1 patient in 100. None of these events was considered serious. The product information contains guidance for doctors on when Zykadia should be interrupted and restarted at a lower dose or stopped altogether. Medicines to manage nausea, vomiting and diarrhoea should be given as appropriate. The product information contains guidance for doctors on when Zykadia should be interrupted and restarted at a lower dose. Heart rate and blood pressure should be checked regularly in patients taking Zykadia. The product information contains guidance for doctors on when Zykadia should be interrupted and restarted at a lower dose or stopped altogether. Important potential risks Risk Nerve damage (neuropathy) Use of Zykadia with other medicines that can affect the way it is broken down in the body (concomitant use of ceritinib and strong CYP3A inhibitors or strong CYP3A inducers ) What is known Damage to nerves which can cause tingling, numbness and weakness has been reported while taking Zykadia but it is not clear if this was a side effect of the medicine. The majority of cases were mild and no patients have discontinued treatment due to these events. There are some medicines that if taken along with Zykadia cause an increase or decrease in the level of ceritinib in the blood. The dose of Zykadia may need to be adjusted by the doctor if use together cannot be avoided. Patients should tell their doctor or pharmacist of any medicines they are taking, plan to take or have recently taken, including medicines obtained without a doctor s prescription. Missing information Risk Use in patients with liver problems (hepatic impairment) What is known Zykadia has not been studied in patients with moderate or severe hepatic impairment. However, as ceritinib is mainly eliminated by the liver, these patients may experience higher levels of the medicine in the body which may last for a longer time. Therefore, Zykadia is not recommended for use in patients with moderate or severe liver problems. Page 3/7

4 Risk Use in patients with severe kidney problems (severe renal impairment) Use in patients with severe heart problems (severe cardiac impairment) Use in elderly patients Use in children (paediatric patients) Use in pregnant and breastfeeding women, and women who are able to become pregnant What is known Only a small amount of ceritinib is eliminated by the kidney. Therefore, in patients with mild or moderate kidney problems, no change in dose is needed. However, it has not been studied in patients with severe kidney problems and Zykadia should be used with caution in this patient population. Patients with heart problems such as heart failure, or who had a heart attack did not participate in the studies. Therefore it is not known whether the effects of the medicine are the same in this group. Few people aged 65 years or older participated in the studies, so there is less information on the effects of Zykadia in this patient population. Only adults participated in these studies, so no data are available in children. Very little information is available on the use of Zykadia in pregnant women. The use of the medicine should be avoided during pregnancy unless the benefits to the mother outweigh any potential risks. Women who are able to become pregnant should use efficient methods of birth control during treatment and for 3 months after stopping the medicine. Long-term safety Effect of Zykadia on other medicines (concomitant use of ceritinib and CYP3A, CYP2C9, CYP2A6 or CYP2E1 substrates; ceritinib and medicines that may prolong the QT interval) Use of Zykadia with other medicines that affect its absorption (concomitant use of ceritinib and proton pump inhibitors [PPIs]) It is also not known whether ceritinib passes into breast milk, and a risk to a breastfed infant cannot be excluded. A decision should therefore be made on whether to stop breastfeeding or avoid treatment with Zykadia. Patients in studies of Zykadia have taken the medicine for about 9 months on average. The safety of Zykadia in patients who have taken the medicine for much longer periods is not known. It is not known if Zykadia could cause changes (either increase or decrease) in the level of certain other medicines if taken together, or may increase the risk of a shared side effect on the heart. Such combinations may need to be avoided or the dose of the other medicine may need to be altered by the doctor. Patients should tell their doctor or pharmacist of any medicines they are taking, plan to take or have recently taken, including medicines obtained without a doctor s prescription. It is not yet known if certain medicines that are used to treat heartburn or stomach ulcers by reducing the production of acid in the stomach could also reduce the amount of Zykadia absorbed and thereby decrease its level in the blood. Patients should tell their doctor or pharmacist of any medicines they are taking, plan to take or have recently taken, including medicines obtained without a doctor s prescription. 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 Page 4/7

5 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 Zykadia can be found on Zykadia s EPAR page. This medicine has no additional risk minimisation measures. Planned post-authorisation development plan List of studies in 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 LDK378A2110/ A Phase I, open label, multicenter, To evaluate the PK (pharmacokinetics - distribution in Use in patients with hepatic impairment Started Final study report Jun-2016 single dose study to evaluate the PK of ceritinib in subjects with hepatic impairment compared to subjects with normal hepatic function. the body) of a single oral dose of ceritinib in subjects with impaired hepatic function as compared to healthy subjects with normal hepatic function. LDK378A2103/ A Phase I, multicenter, open label, To assess the effect of ceritinib on the PK of Concomitant use of ceritinib and CYP2C9 and Planned Final study report Mar-2017 drug-drug interaction study to assess the effect of ceritinib on the pharmacokinetics of warfarin and midazolam administered as a two- drug cocktail in patients with advanced tumors including nonsmall cell lung cancer. warfarin and midazolam administered as a two- drug cocktail in patients with advanced tumours including NSCLC. CYP3A substrates LDK378A2113/ A To assess the Concomitant use Planned Final study report Page 5/7

6 Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results Phase I, single center, openlabel, two-period, single-sequence study to assess the effect of esomeprazole (proton pump inhibitor) on the pharmacokinetics of ceritinib in healthy volunteers. effect of esomeprazole on the PK of a single 750 mg ceritinib dose in healthy adult subjects. of ceritinib and gastric acid reducing agents such as PPIs Mar-2016 LDK378A2303, A Phase III, multicenter, randomized, open-label study of oral LDK378 versus standard chemotherapy in ALK rearranged () advanced nonsmall cell lung cancer who have been treated previously with chemotherapy (platinum doublet) and crizotinib. To compare the antitumour activity of ceritinib versus reference chemotherapy, as measured by length of time patients survive without disease progression (PFS) determined by a committee of independent assessors (BIRC). Confirmatory efficacy data in advanced NSCLC who have been treated previously with chemotherapy (platinum doublet) and crizotinib Ongoing Q LDK378A2201, A Phase II, multicenter, single-arm study of oral ceritinib in ALK-activated NSCLC previously treated with chemotherapy and crizotinib. To demonstrate the antitumour activity of ceritinib, as measured by overall response rate (ORR) by investigator assessment. Supportive efficacy data in advanced NSCLC who have been previously treated with chemotherapy and crizotinib Ongoing Q Page 6/7

7 Studies which are a condition of the marketing authorisation One Phase II study (LDK378A2201) and a Phase III confirmatory study (LDK378A2303), which are currently ongoing, are conditions 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