Rydapt. Summary of the Risk Management Plan (RMP) for Rydapt (midostaurin)

Transcription

1 Regulatory Affairs Rydapt 25 mg soft capsules Summary of the Risk Management Plan (RMP) for Rydapt (midostaurin) Document version: 01 Document status: Document Date: Final 02-June of 6

2 Summary of the Risk Management Plan (RMP) for Rydapt (midostaurin) 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. The RMP summary of Rydapt 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 Rydapt in Switzerland is the Arzneimittelinformation / Information sur le médicament (see approved and authorized by Swissmedic. Novartis Pharma Schweiz AG is fully responsible for the accuracy and correctness of the content of the here published summary RMP of Rydapt. Overview of disease epidemiology Acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer in which the bone marrow makes abnormal myeloblasts (a type of white blood cells), red blood cells or platelets. Every year, between twofour people among are diagnosed with AML. Patients with a permanent change in the deoxyribonucleic acid (DNA) sequence at FLT3 gene may represent between 20%-35% of AML diagnosis and have a worse prognosis compared with those without this change. Patients with a new AML diagnosis are often older. The incidence is similar among patients of different races. Development of AML is considered to be a multistep process that requires the collaboration of several permanent changes of the blood cell's DNA. Risk factors for these changes are specific therapies used for treating malignancies, chemical exposures, although in most instances such a cause cannot be identified. In patients with AML survival after five years following diagnosis ranges between 13%-22%, although it varies with the patients and cancer s characteristics, and some patients can be cured. Advanced Systemic Mastocytosis Mastocytosis is a group of rare disorders that causes the presence of too many mast cells in the body. Advanced systemic mastocytosis (Advanced SM) is a form of this disorder and comprises about 1% - 12% of cases of mastocytosis. While the survival of patients with Advanced SM five years after diagnosis can range between 60%-75%, the survival is significantly worse in patients with MCL. Advanced SM is observed usually in adult Caucasian population and one to three people among 10 million are diagnosed with advanced SM every year. Approximately 90% of adults with mastocytosis have a permanent change in the DNA sequence in the gene encoding the KIT receptor. This stimulates development and expansion of mast cells from blood-forming cells. Patients with Advanced SM present with symptoms and signs related to the mast cell granules in the blood, and these include hypotension, nausea, headache, and fatigue. Additional symptoms include anemia, impairment of liver function, hypertension, skeletal lesions, and malabsorption with weight loss. 2 of 6

3 Summary of treatment benefits In adult patients of with previously untreated acute myeloid leukemia that has a mutation in the FLT3 gene, midostaurin in combination with standard chemotherapy improves survival compared to that in patients treated with a placebo plus chemotherapy. In most of these patients, midostaurin was tolerated adequately. In adult patients with aggressive systemic mastocytosis or mast cell leukemia, including patients with or without an associated hematological non-mast cell disorder (AHNMD), midostaurin produced a response in 60% of patients that was measured as improvement in organ damage caused by mastocytosis. Midostaurin also improved symptoms in many patients and was tolerated adequately in most patients. Unknowns relating to treatment benefits In study CPKC412A2301 of midostaurin combined with chemotherapy in newly diagnosed FLT3-mutated AML, patients were enrolled who were less than 60 of age, and the study provided no information regarding the safety or efficacy of the drug combination in patients 60 years or older. Older patients with newly diagnosed AML can have additional comorbidities that might affect the tolerability of standard and investigational treatments. Nonetheless, during the time that CPKC412A2301 was conducted there has been an emerging awareness that selected fit patients with AML who are 60 years or older can benefit from standard therapy such as was used in this study, although physicians sometime elect to reduce doses such as for high dose cytarabine during consolidation therapy. Despite the absence of this older population in the trial, CPKC412A2301 informs the predicted safety and efficacy of midostaurin in selected older patients. Importantly, although AML in older patients is associated with a higher prevalence of cytogenetic abnormalities that are associated with poor prognosis, the collective evidence does not indicate that the role of mutationally activated FLT3 in the biological behavior or clinical course of AML differs in patients older than age 60. Moreover, studies CPKC412A2104E1 and ADE02T collectively evaluated 126 patients who received midostaurin with chemotherapy with or without hematopoietic stem cell transplant, and the therapy was adequately tolerated. Pharmacokinetics of midostaurin was observed to be similar between the older patients and younger patients. In adult patients, no dose adjustment is recommended based on age. There is at present insufficient information regarding the safety or tolerability of midostaurin in combination with chemotherapy in patients less than 18 years of age. For patients with systemic mastocytosis, the clinical experience of midostaurin is concentrated on patients with advanced SM, and there is insufficient information on the administration of midostaurin to patients with more indolent variants of systemic mastocytosis. Summary of safety concerns Important identified risks Risk What is known Preventability Decrease in the ability of the Some patients who took By having regular blood tests. necessary tissues to produce midostaurin developed 3 of 6

4 white of blood cells (Leukopenia) Severe infections Damage to lungs (Pulmonary toxicity) Interaction with drugs that affect the way midostaurin is broken down in the body (Strong CYP3A4 inhibitors) Interaction with drugs that affect the way midostaurin is broken down in the body (Strong CYP3A4 inducers) leukopenia. In most cases, the leukopenia would resolve (i.e., return to the number of blood cells the patient had before taking midostaurin). Severe infections including sepsis (where the whole body reacts to an infection) and pneumonia are usually frequent in AML and Advanced SM patients. They may occur because these patients have a reduced numbers of white blood cells which help fighting infection. Lung diseases like interstitial lung disease and pneumonitis, in some cases fatal, have occurred in patients treated with midostaurin monotherapy or in combination with chemotherapy. Midostaurin breakdown in the body is done mainly by CYP3A4 (an important protein in the body). Strong CYP3A4 inhibitors decrease CYP3A4 activity, thereby decreasing midostaurin breakdown. Midostaurin breakdown in the body is done mainly by CYP3A4 (an important protein in the body). Strong CYP3A4 inducers increase CYP3A4 activity, thereby increasing midostaurin breakdown. As a result, midostaurin may not be in the body long enough to have an effect. By routine monitoring of the patient. By monitoring the patient for pulmonary symptoms indicative of lung diseases. Treatment with midostaurin and strong CYP3A4 inhibitors at the same time should be avoided. Medications with no or minimal CYP3A4 inhibition must be considered by the patient s physician. Treatment with midostaurin and strong CYP3A4 inducers (promoters) at the same time should be avoided. Medications with no or minimal CYP3A4 induction must be considered by the patient s physician. Important potential risks 4 of 6

5 Risk Heart failure (Cardiac dysfunction) Potential effect on babies in the womb (Reproductive toxicity) Harm from breast-feeding (Toxicity in breastfeeding infants) Interaction with drugs that affect the way midostaurin is broken down in the body (Drugdrug interactions with OATP1B1 transporter substrates) Interaction with drugs that affect the way midostaurin is broken down in the body (Drugdrug interactions with substrates for CYP 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1) Missing Information Risk Use in pediatric population Use in patients with severe hepatic impairment What is known Some patients who received midostaurin in advanced SM studies experienced heart failure symptoms Studies in animals have shown that midostaurin is harmful to the developing foetus. However, the risk in human beings is not known. Hence, midostaurin is not recommended during pregnancy or in women of childbearing potential not using contraception. Pregnant women should be advised of the potential risk to the foetus. If pregnancy occurs during treatment, the patient must be informed of the potential risk to the foetus. It is unknown whether midostaurin or its active metabolites are excreted in human milk. There are no data on the effects of midostaurin on the breast-fed child or the effects of midostaurin on milk production. Midostaurin has shown to increase the effect of certain proteins (OATP1B1 transporter substrates) in studies. Midostaurin treatment could affect other drugs taken by the patient which are metabolized by these proteins. Midostaurin has shown to increase the effect of certain proteins (CYP 1A2, 3A4, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1) in studies. Midostaurin treatment could affect other drugs taken by the patient which are metabolized by these proteins. What is known The safety and efficacy of midostaurin in pediatric patients (0-18 years) have not been established. Hence midostaurin is not recommended for use in children or adolescents under 18 years of age. The safety and efficacy of midostaurin in patients with severe (Child-Pugh C) hepatic impairment have not been established. Hence midostaurin is not recommended for use in patients with severe hepatic impairment Summary of additional risk minimization measures by safety concern 5 of 6

6 All medicines have a Product Information which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimizing them. A shortened version of this information in lay language is provided in the form of the package leaflet (patient information). The measures in these documents are known as routine risk minimization measure. This medicine has no additional risk minimization measures. Planned post-authorization development plan Not applicable as no further studies are planned for the post-authorization development plan. Studies which are a condition of the marketing authorization Not applicable as no studies are a condition of the marketing authorization. Summary of changes to the risk management plan over time Not applicable, as this is the first version of the RMP. This summary is based on EU RMP v1 (date of final sign off: 13-Jul-2016) and was prepared in June of 6