Drug Regulatory Affairs. Lyxumia. Summary of the Risk Management Plan (RMP) for Lyxumia (lixisenatide)

Transcription

1 Drug Regulatory Affairs Lyxumia Summary of the Risk Management Plan (RMP) for Lyxumia (lixisenatide) Document version: 02 Document date: 08-Mar

2 Summary of the risk management plan (RMP) for Lyxumia (lixisenatide) 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 minimize them. An updated version of the global RMP will be submitted as part of the PBRER submission. As the changes also impact the RMP summary, an updated version of the same is also being submitted. The RMP summary of Lyxumia 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 Lyxumia in Switzerland is the Arzneimittelinformation/ Information sur le médicament (see approved and authorized by Swissmedic. Sanofi-aventis (suisse) is fully responsible for the accuracy and correctness of the content of this published summary RMP of Lyxumia. Overview of disease epidemiology Diabetes has become a major health concern worldwide. Type 2 diabetes mellitus is the most common type of diabetes and is increasing all over the world. In the European Union, the proportion of the population with type 2 diabetes mellitus ranges from 2 percent up to 24 percent among people over 20 years of age. Many factors may predispose people to developing type 2 diabetes mellitus. Genetic connections have been identified including family history of diabetes or certain ethnic backgrounds. However, factors related to the lifestyle including excess of calories in the diet, smoking, and alcohol consumption also play an important role in the development of type 2 diabetes mellitus and its complications. Several complications may occur in patients with type 2 diabetes mellitus including problems in the heart, blood vessels, kidneys, eyes and nervous system which increase a person s risk of death. Diseases of the heart and blood vessels, also called cardiovascular diseases are the most common cause of death in diabetic patients. This shows importance of following the diet and treatment recommendations from the treating physicians. Summary of treatment benefits Lixisenatide is a medication used for treatment of type 2 diabetes to lower glucose levels. It belongs to a class of medications called glucagon-like peptide-1 (GLP-1) receptor agonist. Lixisenatide increases the release of insulin from the pancreas and decreases glucagon which is a hormone that has the opposite effect of insulin. Lixisenatide also slows the emptying of the stomach and thus food stays longer in it, it helps in decreasing appetite and reducing body weight. Lixisenatide is used in the treatment of adults with type 2 diabetes mellitus, in combination with oral anti-diabetics and/or in combination with basal insulin. With a cumulative exposure to lixisenatide of patient-years in clinical trials, treatment with lixisenatide in association with other antidiabetic medications demonstrated significant effects in decreasing blood glucose with the associated benefit of reducing body weight. 2

3 Unknowns relating to treatment benefits Lixisenatide has been extensively studied in adults with type 2 diabetes mellitus. However, lixisenatide has not been studied in children younger than 18 years and therefore it is not recommended in this younger age group. Also, there is limited experience in patients with severe kidney disease (renal impairment). Additional studies are currently ongoing and will provide additional data in these groups of patients. Summary of safety concerns Table 1 - Important Risk What is known Preventability Inflammation of pancreas (Pancreatitis) GLP-1: Glucagon-Like Peptide-1. Pancreatitis has been previously identified as a potential safety issue for other drugs in the same pharmacological class (GLP-1 receptor agonists). Few cases of pancreatitis were reported in patients receiving lixisenatide. Symptoms of acute pancreatitis include: persistent, severe stomach pain. If pancreatitis is suspected, lixisenatide should be discontinued; if acute pancreatitis is confirmed, lixisenatide should not be restarted. If you had pancreatitis in the past you should talk to your doctor if lixisenatide is right for you. Table 2 - Important potential risks Risk Thyroid cancer (Medullary thyroid cancer) Pancreatic cancer (Pancreatic cancer) Cancer (Malignant neoplasm) What is known Medullary thyroid cancer is a rare type of cancer that was observed in some animal studies of this class of medications. No risk of medullary thyroid cancer was found in patients treated with lixisenatide. In animal studies with other antidiabetic medications of the same class as lixisenatide, changes in the pancreas were seen. It is not known if treatment with lixisenatide could cause pancreatic cancer in humans. In animal studies with other antidiabetic medications of the same class as lixisenatide, development of cancers was observed. The potential risk of Thyroid cancer is previously described. It is not known if treatment with lixisenatide could cause cancer in humans. Table 3 - Missing information Risk Use in children and adolescents <18 years Use in patients with severe renal impairment (with and without low body weight) What is known The safety and efficacy of lixisenatide in children and adolescents less than 18 years of age has not yet been established. Lixisenatide is not recommended in patients with severe renal impairment or end-stage renal disease. 3

4 Summary of additional risk minimization measures by safety concern All medicines have a summary of product characteristics which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimizing them. An abbreviated version of this in lay language is provided in the form of the package leaflet. The summary of product characteristics and the package leaflet for lixisenatide can be found in the lixisenatide European Public Assessment Reports page. There are no additional non routine risk minimization measures. post-authorization development plan The planned post-authorization development plan for lixisenatide is described in the below table. Table 4 - List of studies in post-authorization development plan Study/activity (including study number) Objectives Safety concerns/efficacy issue addressed Status date for submission of (interim and) final results EFC12382: Phase 3 study using lixisenatide in patients not well controlled with basal insulin evaluate the effects of lixisenatide in the control of blood glucose and HbA1c when used with a basal insulin. 75 years Sep-2016 EFC11476: A Phase 3 study to evaluate the use of lixisenatide in pediatric patients (10-17 years old) with type 2 diabetes mellitus (PIP) assess the effect and safety of lixisenatide for the treatment of type 2 diabetes mellitus in children aged between years. Use in children and adolescents <18 years Efficacy in children/adolescents 10 to 18 years (start in Q2 2018) Q TDR14311: A 6-week randomized, doubleblind, placebo-controlled, dose escalation study on safety, pharmacokinetics and pharmacodynamics of lixisenatide in pediatric patients with type 2 diabetes To measure the amount of study medication in the body of children of different agegroups and how long it stays in their body. To demonstrate the relationship between the amount of lixisenatide in the body and the effect on reduction of the blood glucose level after caloric drink intake. To support the selection of optimum safe dose for further clinical trials. Use in children and adolescents <18 years Centers open, no patient included as of RMP DLP Final report in Q Pharmacoepidemiology study: Retrospective study on the risk of Acute pancreatitis, Pancreatic describe the occurrence of pancreatitis, pancreatic cancer and thyroid cancer in Pancreatitis, pancreatic cancer, and thyroid cancer, in particular medullary thyroid cancer Sep

5 Study/activity (including study number) Objectives Safety concerns/efficacy issue addressed Status date for submission of (interim and) final results cancer, and Thyroid cancer in patient using drugs of similar class as lixisenatide (GLP-1 receptor agonists) patients receiving drugs of similar class as lixisenatide (GLP-1 receptor agonists) and in patients receiving other types of antidiabetic treatments using the existing data from national registers and databases in Belgium and Italy. Pharmacoepidemiology study: Patient Registry of Lixisenatide Use in Adult Type 2 Diabetes monitor the occurrences of pancreatitis, pancreatic cancer and thyroid cancer in patients treated with lixisenatide using the data from national registers and databases in Italy and Belgium. Pancreatitis, pancreatic cancer, and thyroid cancer, in particular medullary thyroid cancer Started Annual progress reports starting in Q Dec-2020 for acute pancreatitis and cancer events of interest EFC11319/ELIXA: Longterm Phase 3 cardiovascular outcomes study determine the risk of cardiovascular adverse events (heart attack, heart failure, and stroke) in patients receiving lixisenatide. Primarily cardiovascular safety. Also relevant for other identified and potential risk (pancreatitis, pancreatic cancer, medullary thyroid cancer, malignant neoplasms) and missing information (use in patients 75 years, and patients with renal impairment) in Sep-2015 EFC12261: Phase 3 study comparing lixisenatide injected before the main meal of the day with lixisenatide injected before breakfast evaluate the control of blood glucose and HbA1c when lixisenatide is injected before the main meal of the day compared to lixisenatide injected before breakfast in patients not having a good control only with metformin use. 75 years, and patients with renal impairment on 25-Mar-2014 (within variation II/0004) EFC12626: A Phase 3 study comparing lixisenatide to short acting insulin glulisine (once daily or three times daily) in patients not well controlled with basal insulin demonstrate lixisenatide has similar beneficial effects in blood glucose and HbA1c as the short acting insulin glulisine (once daily or three times daily). 75 years, and patients with renal impairment on 29-Jun-2015 (within variation II/0012) EFC12703: A Phase 3 study to evaluate lixisenatide use in older patients not well controlled with their current evaluate the effect of lixisenatide on the blood glucose and HbA1c in older primarily in Sep

6 Study/activity (including study number) Objectives Safety concerns/efficacy issue addressed diabetes treatment patients. in patients 75 years as well as in patients with renal impairment. Efficacy in patients >70 years of age. Status date for submission of (interim and) final results PDY12625: A phase 3 study on pharmacodynamic effects of treatment with lixisenatide compared to liraglutide in patients with type 2 diabetes not well controlled with their current diabetes treatment. evaluate the effect of lixisenatide on the blood glucose after 8-week treatment period. 75 years, and patients with renal impairment on 28-Jul-2014 (within variation II/0007) PKD11475: A phase 1 study to evaluate lixisenatide in pediatric patients (10-17 years old) with type 2 diabetes study the effect of lixisenatide in decreasing the blood sugar after a meal (post-prandial glucose) in type 2 diabetic children (pediatric) (10-17 years of age) in comparison with adults ( 18 years of age). Use in children and adolescents <18 years on 11-Dec-2014 (within Art 46 procedure P46/013) GLP-1: Glucagon-Like Peptide-1; CSR: Clinical Study Report; HbA1c: Glycosylated Hemoglobin; RMP: Risk Management Plan; PIP: Pediatric Investigational Plan. None of the above studies are condition(s) of the marketing authorization. Summary of changes to the RMP over time Table 5 - Summary of changes to the Risk Management Plan over time Version Date Safety concerns Comment Feb-2014 Pancreatitis escalated to an important identified risk May-2014 Pancreatic cancer (extracted from the unspecific Malignant neoplasm potential risk) added as an important potential risk Sep-2015 Important identified risk of Pancreatitis is changed to Pancreatitis (class risk not confirmed with lixisenatide data). Cardiovascular events are deleted from important potential risks. Pancreatic cancer is deleted from important potential risks. The use in very elderly ( 75) years in not a missing information anymore. The use in patients with moderate 6 Submission initiated by European Medicines Agency request for harmonization of safety concerns for GLP-1 based therapies Submission initiated by European Medicines Agency request for harmonization of safety concerns for GLP-1 based therapies Submission in the context of a variation following the completion of studies in older patients and cardiovascular outcome study (EFC12703 and EFC11319). The new data of these studies are supporting the changes in the list of safety concerns.

7 Version Date Safety concerns Comment renal impairment in not missing information anymore Jan-2016 Important identified risk of Pancreatitis (class risk not confirmed with lixisenatide data) is changed to Pancreatitis Pancreatic cancer is added to important potential risks. Reintroduced following PRAC and CHMP comments. Reintroduced following PRAC and CHMP comments Sep-2016 None Update of pharmacovigilance plan submitted reports Jun-2017 List of safety concerns revised: deletion of important risks/missing information LSC revised to implement CHMP and PRAC Rapporteurs comments raised in the Renewal Preliminary Joint Assessment Report; Update of Part III including a brief summary of EFC12382 study results following CHMP Opinion adopted on 15-Dec-2016 for procedure EMEA/H/C/002445/II/0020 and revised milestones for the availability of the final report of the ongoing Patient Registry (pharmacoepidemiology program); Integration of routine updates in the frame of the first EU Renewal application (eg, epidemiology, clinical trial exposure, post-authorization experience). GLP-1: Glucagon-Like Peptide-1; PRAC: Pharmacovigilance Risk Assessment Committee; CHMP: Committee for Medicinal Products for Human Use; EU: European Union; EMEA: European Medicines Agency. 7