Swiss Summary of the Risk Management Plan (RMP) for BLINCYTO (Blinatumomab)

Transcription

1 Swiss Summary of the Risk Management Plan (RMP) for BLINCYTO (Blinatumomab) RMP Summary: Version 1, April 2017 EU RMP: Version 3.2, November 2016 Page 1 of 13

2 The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier for market approval of a medicine. The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimise them. The RMP summary of BLINCYTO is a concise document and does not claim to be exhaustive. As the RMP is an international document, the summary might differ from the Arzneimittelinformation / Information sur le médicament approved and published in Switzerland, e.g. by mentioning risks occurring in populations or indications not included in the Swiss authorization. Please note that the reference document which is valid and relevant for the effective and safe use of BLINCYTO in Switzerland is the Arzneimittelinformation/ Information sur le médicament (see approved and authorized by Swissmedic. AMGEN Switzerland AG is fully responsible for the accuracy and correctness of the content of the published summary RMP of BLINCYTO. Page 2 of 13

3 Overview of disease epidemiology Blincyto is a cancer medicine used to treat adult patients with B-precursor acute lymphoblastic leukaemia (ALL), a type of blood cancer. In B-precursor ALL, certain cells that give rise to B-cells (a type of white blood cell) multiply too quickly and eventually these abnormal cells replace normal blood cells. Blincyto is used when the ALL has come back or has not responded to previous treatment. It is used when the patients are Philadelphia-chromosome-negative (Ph-). This means that they do not have the Philadelphia chromosome, a special chromosome formed when some of the genes are re-arranged, and which is found in some patients with ALL. Acute lymphoblastic leukemia occurs in approximately 27 of every 100,000 people in the European Union. Approximately 40% of the cases are in adults. Risk factors for acute lymphoblastic leukemia include gender (male), race (white), and age (above 70 years). Approximately 35% of patients aged 18 to 60 years with acute lymphoblastic leukemia survive for at least 5 years or longer. Summary of treatment benefits Blincyto contains blinatumomab, a type of antibody, as the active substance. It has been studied in one main study in 189 patients with Ph- B-cell precursor ALL whose leukaemia had come back or had not responded to treatment. Patients were given Blincyto for up to five treatment cycles. In this study, Blincyto was not compared with any other treatment. The main measure of effectiveness was based on the percentage of patients who, after two treatment cycles, responded to treatment, measured as resolution of signs of leukaemia and complete or partial normalisation of blood cell counts. The study showed that 42.9% (81 out of 189) of patients given Blincyto responded to treatment. In those patients who had a response, in most cases there was no evidence of cancer cells left. The average survival time before the cancer came back was around 6 months, which could enable suitable patients to undergo a blood stem cell transplant. Unknowns relating to treatment benefits The treatment benefits of Blincyto have not been studied in certain populations such as patients with liver or kidney disease, HIV positive patients or patients with hepatitis B or C infection, children and adolescents, elderly patients and patients receiving other cancer medicines (such as immunotherapy or radiotherapy). Page 3 of 13

4 Summary of safety concerns Important identified risks Risk What is known Preventability Neurological problems (problems affecting the function of the brain and/or nerves) Infections Immune system reactions (cytokine release syndrome) Neurological problems (such as fits, problems with speech, alterations in consciousness, confusion and disorientation, problems with balance and coordination) occur in approximately 50% of patients treated with Blincyto. Patients treated with Blincyto are at a higher risk of infections including fungal, bacterial and viral infections. Patients treated with Blincyto are at higher risk of experiencing cytokine release syndrome (a complication due to massive release in the blood of proteins which stimulate inflammation). Symptoms include Patients should talk to their doctor, pharmacist or nurse before using Blincyto if they have ever had neurological problems (for example fits, memory loss, confusion, disorientation, loss of balance, difficulty in speaking). Patients should immediately inform their doctor, pharmacist or nurse if they experience fits, difficulty in speaking, confusion and disorientation or loss of balance. It is recommended that a neurological examination is performed in patients before starting Blincyto therapy and that patients are clinically monitored for signs and symptoms of neurologic events (e.g. writing test). In case of neurological problems treatment may have to be interrupted. In patients who develop fits, anticonvulsant medicines may be needed. Patients should talk to their doctor, pharmacist, or nurse before using Blincyto if they have an infection. Patients should take their temperature as they may have a fever. Patients should tell their doctor or nurse immediately if they develop chills or shivering, or feel warm these may be symptoms of an infection. In case patients develop an infection during treatment with Blincyto, treatment may have to be interrupted. Before the patient receives Blincyto, other medicines will be given to help reduce the risk of cytokine release syndrome. Patients should be closely monitored for signs and symptoms of these events. Page 4 of 13

5 Risk What is known Preventability fever, swelling, chills, decreased or increased blood pressure, and fluid in the lungs, which may become severe. Infusion-related reactions Complications due to the break down of cancer cells (tumor lysis syndrome) Leakage of fluid from small blood vessels (capillary leak syndrome) Elevated liver enzymes Mistakes when preparing or giving Blincyto treatment (medication errors) Blincyto is given as an infusion into a vein. Reactions related to the infusion of Blincyto may include, wheezing, flushing, face swelling, difficulty breathing, low blood pressure and high blood pressure. Patients treated with Blincyto may get complications due to the break down of their cancer cells. This can lead to increased blood levels of potassium, uric acid, and phosphorus and decreased blood levels of calcium. Patients treated with Blincyto may get leakage of fluid from small blood vessels. This can cause pain and swelling of the affected area(s) and low blood pressure. Patients treated with Blincyto may get high levels of liver enzymes in blood tests. This could be a sign of liver problems. If this happens, it usually occurs at the beginning of treatment. Blincyto is infused continuously using a pump device. Mistakes when preparing or giving the Blincyto infusion can result in patients getting a dose that is too high or too low. Mistakes in setting up the pump, or problems with the pump can also cause medication errors. Before the patient is given treatment with Blincyto, other medicines will be given to help reduce infusion reactions and other possible side effects. Patients will be monitored for tumor lysis syndrome during treatment with Blincyto and may be given fluids to help prevent it. Patients should be closely monitored for tumor lysis syndrome (including renal function and fluid balance) for the first 48 hours after their first infusion. Patients who develop tumor lysis syndrome may have to stop taking Blincyto Patients treated with Blincyto and who develop capillary leak syndrome should be managed promptly. Liver enzyme levels should be regularly monitored during treatment. Detailed instructions are provided to healthcare professionals who prepare and give Blincyto treatment. Patients should tell their doctor or nurse immediately if they notice any problems with their infusion pump. Decreased levels of white blood cells with or without fever (febrile neutropenia/ neutropenia) Treatment may result in a very low white blood cell count (neutropenia) or very low white blood cell count with a fever (febrile neutropenia). The blood counts should be regularly monitored during treatment, especially during the first 9 days of the first cycle. Page 5 of 13

6 Risk What is known Preventability Low levels of antibodies called immunoglobulins which help the immune system fight infection Inflammation of the pancreas (pancreatitis) Patients treated with Blincyto may have a reduction in their levels of immunoglobulins. This may make them more likely to get infections. Patients receiving Blincyto may develop inflammation of the pancreas, which can be lifethreatening or cause death. Treatment with high-dose steroids may have contributed in some cases to inflammation of the pancreas. Patients should measure their body temperature if they develop chills or shivering, or feel unusually warm. They may have a fever, a sign of an infection. Patients should tell their doctor or nurse immediately if they develop severe and persistent stomach pain with or without nausea and vomiting as these may be symptoms of inflammation of the pancreas Important potential risks Risk Off-label use (Use of Blincyto for diseases other than adults with Philadelphia chromosome negative (Ph-) relapsed or refractory acute lymphoblastic leukemia) Changes to the white matter of the brain (leukoencephalopathy [including progressive multifocal leukoencephalopathy, a rare viral disease]) Blood clots (thromboembolic events), including disseminated intravascular coagulation Risk of antibody production against Blincyto (immunogenicity) which may result in a lack of effect or allergic reactions What is known Blincyto should not be used for diseases other than Ph- relapsed or refractory acute lymphoblastic leukemia. Some patients have developed changes of the brain (leukoencephalopathy) during treatment with Blincyto. It is not yet known whether these changes were due to Blincyto treatment, or were due to other medical conditions and treatments that these patients had. Because of the potential for progressive multifocal leukoencephalopathy (PML), patients should be monitored for signs and symptoms. If these are consistent with PML events, the doctor should consider referral to a neurologist, brain MRI and examination of cerebral spinal fluid. No cases of PML were reported during the main study with Blincyto. Blood clots (venous thromboembolism) in the veins can occur commonly in patients with cancers. Some patients being treated with Blincyto have experienced thromboembolic events including disseminated intravascular coagulation (a condition in which blood clots form in blood vessels throughout the body, potentially cutting off the supply to organs). However the relationship to Blincyto is unclear. With any medicine that is a protein (such as an antibody) there is a potential for the body to recognise the protein as foreign and create antibodies to neutralise it. While a small number of patients have developed antibodies to Blincyto, this did not impact its activity, so Blincyto was still effective. Page 6 of 13

7 Risk What is known Use in patients with existing liver problems (hepatic impairment) Use in patients with active or history of high risk neurological (central nervous system) pathology including patients with untreated acute lymphoblastic leukemia in the central nervous system Blood disorders, particularly decrease in the level of a certain type of white blood cell (B cell) in newborns exposed to Blincyto in pregnant women Blincyto has not been studied in patients with liver disease; however, it is not expected to be harmful to the liver. For patients with relevant neurological pathology (e.g. epilepsy, stroke, Parkinson s disease), the potential benefits of treatment should be carefully weighed against the risk of neurological events and caution should be exercised when administering Blincyto. It is recommended that a neurological examination is performed in patients before starting Blincyto therapy and that these patients are clinically monitored for signs and symptoms of neurological events (e.g. writing test). There is little experience with Blincyto in patients who have leukaemia cells in the brain or cerebrospinal fluid. However patients have been treated with Blincyto in clinical studies after clearance of ALL by directly infusing Blincyto in the brain/spinal cord areas (such as intrathecal chemotherapy). Therefore once the ALL is cleared in brain/spinal cord areas, treatment with Blincyto may be initiated. The effects of Blincyto in newborns are unknown. Blincyto could reduce the activity of the immune system in the newborn. Blincyto should not be used in pregnancy unless the potential benefits outweigh the potential risk to the fetus. If women are pregnant, think they may be pregnant or planning to have a baby, they should consult their doctor or nurse for advice before taking Blincyto. Missing information Risk Use in pregnancy and breastfeeding Use in children Use in the elderly Use in patients with existing kidney problems (renal impairment) What is known The effects of Blincyto in pregnant and breastfeeding women are unknown. If women are pregnant, think they may be pregnant or planning to have a baby, they should consult their doctor or nurse for advice before taking this medicine. Women should not breastfeed during, and 48 hours after, finishing treatment with Blincyto. Blincyto should not be used in children below 18 years of age. There is limited information in patients aged 75 years or above. However, patients aged 65 years or above experienced more serious neurologic events than subjects younger than 65. Blincyto has not been studied in patients with kidney disease; however, it is not expected to be harmful to the kidneys. Clearance values in renal impaired patients were within the range observed in patients with normal renal function, and therefore no clinically meaningful impact of renal function on clinical outcomes is expected. Page 7 of 13

8 Risk What is known Patients of different ethnic origins Patients with active uncontrolled infections Use in patients with human immunodeficiency virus positivity or chronic infection with hepatitis B virus or hepatitis C virus Use in patients after recent blood (haematopoietic) stem cell transplantation Recent or concomitant treatment with other cancer therapies (including radiotherapy) Recent or concomitant treatment with other immunotherapy Effects on fertility Long-term safety Most of the people who participated in studies with Blincyto were Caucasian (white). More information is needed to determine the effect of ethnic origin on either the efficacy or safety of Blincyto. Blincyto is not intended for patients with active uncontrolled infections. In patients who are using Blincyto and who develop infections, treatment may have to be discontinued. Blincyto has not been studied in patients infected with HIV (human immunodeficiency virus) or with chronic infection with hepatitis B virus or hepatitis C virus. Blincyto has not been studied in patients after recent blood (haematopoietic) stem cell transplantation. Blincyto has not been studied in patients receiving recent or concomitant treatment with other cancer therapies, including radiotherapy. Blincyto has not been studied in patients receiving recent or concomitant treatment with other immunotherapy. The effect on fertility has not been established. The long term effects of Blincyto have not been established. 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. This medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). Full details on these conditions and the key elements of any educational material can be found in Annex II of the product information which is published on Blincyto s EPAR page; how they are implemented in each country however will depend upon agreement between the marketing authorisation holder and the national authorities. Page 8 of 13

9 These additional risk minimisation measures are for the following risks: Neurological events and medication errors Risk minimisation measure: Educational materials for doctors, pharmacists, nurses, and patients (including caregivers). In addition, patients will also receive a patient alert card. Objective and rationale: To provide advice on how to prevent neurological events; to reduce the risk of medication errors. Description: Educational material will be provided to patients, caregivers, doctors, nurses and pharmacists. These will stress the importance of reporting side effects, how to administer Blincyto and how to reduce the risk of medication errors while using the infusion pump. It will also include a description of the main signs and/or symptoms of neurological events and the importance of notifying the treating doctor or nurse immediately if symptoms occur. 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 Study (TOWER): A phase 3, randomized, open label study to investigate the efficacy of the BiTE Antibody Blinatumomab Versus Standard of Care Chemotherapy in Adult Subjects Primary objective: - To evaluate the effect of Blincyto on overall survival when compared to standard of care chemotherapy. This study will provide a more complete dataset from which to evaluate overall survival seen with Blincyto and will help to better differentiate between the adverse events associated with Blincyto and those associated with cytotoxic chemotherapy in a heavily pretreated patient population with a rapidly progressing disease Ongoing Q With Relapsed/ Refractory B precursor Acute Lymphoblastic Leukemia (ALL) Page 9 of 13

10 Study/activity (including study number) Study : An observational study of Blincyto safety and effectiveness, utilisation, and treatment practices Objectives Primary objective: - To characterise the safety profile of Blincyto in routine clinical practice in countries in the EU. - To estimate the frequency and types of Blincyto medication errors identified. Secondary objectives: - To estimate the incidence of other serious adverse events, ie, serious adverse events not included in the primary objective. - To evaluate safety and effectiveness endpoints among patient subgroups defined by demographic and clinical factors. - To characterise the effectiveness of Blincyto in routine clinical practice. - To describe Blincyto utilisation and select healthcare resource use in routine clinical practice. Safety concerns /efficacy issue addressed Selected identified risks, potential risks, and missing information, as well as other serious adverse events Status Planned Planned date for submission of (interim and) final results Protocol to be developed within 2 months of EC Decision Enrolment update will be provided in each PSUR Annual interim reports will be provided with corresponding PSUR starting with PSUR #3 Final CSR anticipated Q Page 10 of 13

11 Study/activity (including study number) Study : Survey of physicians, pharmacists, and nurses involved in the prescribing, preparation and administration of Blincyto in Europe to evaluate the effectiveness of additional risk minimization measures Objectives Primary objective: - To evaluate the distribution, knowledge and effectiveness of additional risk minimisation measures for physicians, pharmacists and nurses. Safety concerns /efficacy issue addressed Neurological events, medication errors Status Planned Planned date for submission of (interim and) final results Final CSR anticipated Q Study : A cross sectional survey of patients and caregivers receiving Blincyto in routine clinical practice in Europe to evaluate the effectiveness of additional risk minimization measures Primary objective: - To assess knowledge about and receipt of the educational materials. Secondary objective: - To determine the level of understanding of the information in the educational materials. Neurological events, medication errors Planned Final CSR anticipated Q To evaluate adherence to the instructions in the patient educational materials. Page 11 of 13

12 Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results Study MT : A phase 1/2, single-arm, dose finding/efficacy study in patients < 18 years with B precursor ALL in second or later bone marrow relapse, in any marrow relapse after allogeneic HSCT, or refractory to other treatments; > 25% blasts in bone marrow Study MT (extension cohort only): An openlabel, multicenter, phase 2 study to evaluate efficacy and safety of the bi-specific T-cell engager (BiTE) antibody Blincyto in adult subjects with relapsed/ refractory B- precursor acute lymphoblastic leukemia (ALL) - To determine the recommended phase 2 dose of Blincyto - To assess the efficacy of Blincyto - To evaluate CNS symptoms and explore potential predictive factors for CNS events associated with Blincyto Pediatrics Ongoing Primary CSR: 15 December 2015 Neurologic events Ongoing Final CSR: June 2018 Page 12 of 13

13 Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results Study : A Randomized, Open-Label, Controlled Phase 3 Adaptive Trial to Investigate the Efficacy, Safety, and Tolerability of the BiTE Antibody Blincyto as Consolidation Therapy Versus Conventional Chemotherapy in Pediatric Patients with High-Risk First Relapse of B- precursor Acute Lymphoblastic Leukemia (ALL) -To evaluate event-free survival (EFS) in the Blincyto arm versus EFS in the standard consolidation chemotherapy arm Pediatric patients Ongoing Final CSR: July 2024 Studies which are a condition of the marketing authorisation Study and Study are conditions of the marketing authorisation. Summary of changes to the risk management plan over time Major changes to the Risk Management Plan over time Not applicable. This summary was last updated in April Page 13 of 13