VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Chronic lymphocytic leukaemia 1 Chronic lymphocytic leukemia (CLL) is a condition characterized by a progressive accumulation of functionally incompetent lymphocytes (a type of white blood cell). It is the most common form of leukemia found in adults in Western countries. Some patients die rapidly, within 2-3 years of diagnosis, because of complications from CLL, but most patients live 5-10 years. Patients with CLL have a higher-than-normal white blood cell count, which is determined by complete blood count (CBC). As in the case of most malignancies, the exact cause of CLL is uncertain. The incidence of CLL is higher among whites than blacks. The incidence of CLL is higher in males than in females, with a male-to-female ratio of 1.7:1. During the later phase, morbidity is considerable, both from the disease and from complications of therapy. Indolent non-hodgkin's lymphomas (cancer of the lymph nodes) 2
Non-Hodgkin's lymphoma (NHL) is the most frequent blood cancer, representing approximately 4% of all cancer diagnoses. NHL is more than 5 times as common as Hodgkin disease. Incidence varies with race; white people have a higher risk than black and Asian American people. In general, the incidence of NHL is slightly higher in men than in women, with a male-to-female ratio of approximately 1.4:1. The median age at presentation for most subtypes of NHL is older than 50 years. NHL is a complex group of more than 45 distinct varieties, divided into two categories: The aggressive types of cancer of lymph nodes The indolent (slow growing) types of cancer of lymph nodes The indolent forms are usually not curable, but patients often live for many years with them because they respond very well to treatment and remain in remission for long periods due to their slow growth. Multiple myeloma (MM) (multiple bone marrow cancer) 3 MM accounts for 10% of all blood cancers. The age-adjusted annual incidence of MM is 4.3 cases per 100,000 white men, 3 cases per 100,000 white women, 9.6 cases per 100,000 black men, and 6.7 cases per 100,000 black women. The median age of patients with MM is 68 years for men and 70 years for women. Only 18% of patients are younger than 50 years, and 3% of patients are younger than 40 years. The male-to-female ratio of multiple myeloma is approximately 3:2. MM has a survival ranging from 1 year to more than 10 years. Median survival in unselected patients with MM is 3 years. Survival is higher in younger people and lower in the elderly. Genetic factors, environmental/occupational factors or radiation represent possible causes for MM. VI.2.2 Summary of treatment benefits A clinical trial was conducted in 301 previously-untreated patients with Binet Stage B or C. Patients were randomly assigned to receive either bendamustine at 100 mg/m 2 or chlorambucil at 0.8 mg/kg. The results demonstrated a higher rate of overall response (90 vs 38) and a longer progression-free survival (18 months vs 6 months) for bendamustine compared to chlorambucil (Knauf WU et al, 2009; Treanda US Prescribing Information, 2008). One hundred patients with indolent B-cell non Hodgkin s lymphomas refractory to rituximab were treated with bendamustine monotherapy 120 mg/m² i.v. on Days 1 and 2 planned for at least 6 cycles. The overall response rate was 75% (17% complete and 58% partial). The median duration of remission was 40 weeks. (Levact SmPC, 2012). A study performed on 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen showed an overall response rate of 77% (15% complete response, 19% unconfirmed complete response, and 43% partial) after treatment with bendamustine, 120 mg/m 2, on Days 1 and 2 of a 21-day treatment cycle. Patients were treated for up to 8 cycles. The median duration of response was 9.0 months for patients with indolent disease (Friedberg JW et al, 2008). A study compared bendamustine and prednisone (BP) (n=68) to standard melphalan and prednisone (MP) (n=63) treatment in previously untreated patients with Multiple Myeloma. The overall response rate was 75% in the BP and 70% in the MP group. A significantly higher number of patients treated with BP achieved a complete remission than did patients receiving MP (32 vs. 13%), and the maximum response was achieved more rapidly in patients treated with BP compared to those receiving MP (6.8 vs. 8.7 cycles) (Ponisch W et al, 2006). VI.2.3 Unknowns relating to treatment benefits At present no data is available in patients with severe hepatic impairment and there is no experience in children and adolescents with bendamustine. No clinical data regarding race differences in bendamustine use is available. Furthermore, there are insufficient data from the PhV-20141021 Page 64/110
use of bendamustine in pregnant women and it is not known whether bendamustine passes into breast milk. Acknowledging this missing information, there is no evidence to suggest that treatment results would be different in any subgroup of the target population, for any of the indications.. VI.2.4 Summary of safety concerns Important identified risks Risk What is known Preventability Reduced bone marrow activity (Myelosuppression) Infections Human body incapacity to eliminate waste products from the dying cancer cells (Tumour lysis syndrome) Severe over sensitivity reactions (severe hypersensitivity reactions) The dose-limiting side-effect of bendamustine is impaired bone-marrow function, which usually returns to normal after treatment. Suppressed bone marrow function increases the risk of infection. If it is used in combination with medicines which inhibit the formation of blood in the bone marrow, the effect on the bone marrow may be intensified. treatment may affect patients immune system which can further predispose them to infections. Signs of infections include fever or lung symptoms. If bendamustine is used in combination with medicines which alter the immune response, this effect may be intensified. Cytostatic medicines may diminish the effectiveness of live virus vaccination. Additionally cytostatic medicines increase the risk of an infection after vaccination with live vaccines When the disease is very severe, the body may not be able to clear all the waste products from the dying cancer cells. This is called tumour lysis syndrome and can cause kidney failure and heart problems within 48 hours of the first dose of bendamustine. Signs of this adverse reaction include pain in the side, blood in the urine or reduced amount of urine. Hypersensitivity symptoms are generally mild (fever, chills, pruritus and rash) but in rare instances severe over sensitivity reactions (anaphylactic reactions) and signs similar to anaphylactic reactions (anaphylactoid reactions) have oc- Yes, by monitoring blood cell counts regularly. must not be used in cases of severely disturbed bone marrow function (bone marrow depression) and serious changes in the number of white blood cells and platelets in the blood. Yes, by monitoring for early symptoms Other medicine may be given to prevent this (e.g. allopurinol) Measures to prevent severe reactions including antihistamines, antipyretics and corticosteroids must be considered in subsequent cycles in patients who have previously experienced infusion reac- PhV-20141021 Page 65/110
Risk What is known Preventability curred. These reactions usually occur tions. after the first exposure. Patients Patients who experienced should pay attention to infusion reactions after your first cycle of therapy. Grade 3 or worse allergic type reactions were typically Severe skin reactions Cardiac disorders Patients are advised to contact their doctor in case of reactions on the skin during treatment with bendamustine. The reactions may increase in severity. A small number of cases of severe skin reactions like Stevens-Johnson Syndrome (serious illness with blistering of the skin, mouth, eyes and genitals) and Toxic Epidermal Necrolysis (serious illness with blistering of the skin) have been reported. Patients should talk to their doctor before or during treatment with bendamustine, in cases of existing heart disease (e.g. heart attack, chest pain, severely disturbed heart rhythms). The following cardiac adverse reactions were reported with bendamustine disturbed function (dysfunction) of the heart, such as feeling your heartbeat (palpitations) or chest pain (angina pectoris); disturbed heart rhythms (arrhythmia); accumulation of fluid in the heart sac (escape of fluid into the pericardial space); increased heart rate (tachycardia); heart attack, chest pain (myocardial infarct); heart failure Cardiac toxicity was also seen in maximum tolerated dose studies. not re challenged. Skin reactions cannot be prevented but if they are progressive, bendamustine should be withheld or discontinued. For severe skin reactions where a relationship to bendamustine is suspected, treatment should be discontinued. During treatment with bendamustine the concentration of potassium in the blood must be closely monitored and potassium supplement must be given when K + < 3.5 meq/l, and ECG measurement must be performed. Important potential risks Risk What is known (Including reason why it is considered a potential risk) Secondary malignancies There have been reports of secondary tumours (myelodysplastic syndrome, acute myeloid leukaemia (AML), bronchial carcinoma) following treatment with bendamustine. No clear relationship with bendamustine could be determined. Renal toxicity Increased blood level of creatinine and increased blood level of urea have been reported Hepatotoxicity Patients should not use bendamustine if they have severe liver dysfunction (damage to the functional cells of the liver). PhV-20141021 Page 66/110
Risk Embryotoxicity, teratogenicity and genotoxicity Missing information Risk Use in severe hepatic impairment Use in patients below 18 years of age Exposure during pregnancy and lactation Effect in different races What is known (Including reason why it is considered a potential risk) A rise in liver enzymes AST/ALT was reported. can cause genetic damage and has caused malformations in animal studies. These are based on the non-clinical studies results. There is insufficient data from the use of bendamustine in pregnant women. Due to this, this risk is classifies as potential. It is recommended not use bendamustine during pregnancy unless certainly indicated by the doctor and, case of treatment, to use medical consultation about the risk of potential adverse effects for the unborn child; genetic consultation is recommended. Man should avoid fathering a child during and for up to 6 months after treatment. What is known No data is available in patients with severe hepatic impairment. Patiens are instructed not to use bendamustine if they have severe liver dysfunction (damage to the functional cells of the liver) or if they have yellowing of the skin or whites of the eyes caused by liver or blood problems (jaundice). There is no experience in children and adolescents with bendamustine. There are insufficient data from the use of bendamustine in pregnant women. During pregnancy bendamustine should not be used unless clearly necessary. If patients are pregnant or breastfeeding, think might be pregnant or are planning to have a baby, to ask their doctor for advice before taking any medicine. It is not known whether bendamustine passes into breast milk, and its use is therefore contraindicated during breast feeding. Breast feeding must be discontinued during treatment with bendamustine. NA VI.2.5 Summary of risk minimisation measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. This medicine has no additional risk minimisation measures. VI.2.6 Planned post authorisation development plan No post-authorisation safety or efficacy studies are ongoing or are planned to be conducted for bendamustine PhV-20141021 Page 67/110
VI.2.7 Summary of changes to the Risk Management Plan over time Version Date Safety Concerns Comment <Identified Risks Potential Risks Missing information> 1.0 04-03-2014 Myelosuppression Infections Tumour lysis syndrome Severe hypersensitivity reactions Skin reactions Embryotoxicity, teratogenicity and genotoxicity Use in severe hepatic impairment 2.0 Addition of severe skin reactions and cardiac disorders as identified reactions Addition of secondary malignancies, renal toxicity and hepatotoxicity as potential risks Removal of skin reactions as a potential risk ( as this is upgraded to identified) Addition of use in patients below 18 years of age, exposure during pregnancy and lactation and effect in different races under missing information Not approved PhV-20141021 Page 68/110