Summary of the risk management plan (RMP) for Gazyvaro (obinutuzumab)

Transcription

1 EMA/319729/2014 Summary of the risk management plan (RMP) for Gazyvaro (obinutuzumab) This is a summary of the risk management plan (RMP) for Gazyvaro, which details the measures to be taken in order to ensure that Gazyvaro 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 Gazyvaro, which can be found on Gazyvaro s EPAR page. Overview of disease epidemiology Gazyvaro is a medicine used for the treatment of chronic lymphocytic leukaemia (CLL). CLL is a rare cancer of B-lymphocytes, a type of white blood cell. Gazyvaro is used in combination with chlorambucil (another cancer medicine), in previously untreated patients who have other medical conditions that make them ineligible for a fludarabine-based cancer treatment. In the European Union, Gazyvaro has been designated an orphan medicine due to the rarity of the condition. In Europe, in 2013, the estimated prevalence of CLL was approximately 3 per 10,000 people. CLL is almost twice as common in men as in women, and its incidence increases with age. Summary of treatment benefits Gazyvaro contains the active substance obinutuzumab, a monoclonal antibody. The medicine was investigated in a main study involving 781 patients with previously untreated CLL. In the study, Gazyvaro was shown to increase the time patients lived without CLL getting worse (progression-free survival) when it was given with chlorambucil. The progression-free survival was on average 26.7 months in patients who received Gazyvaro and chlorambucil, and 11.1 months in those who received chlorambucil alone. The study also showed that progression-free survival is increased in patients given Gazyvaro and chlorambucil those given rituximab (another medicine) and chlorambucil. The progression-free survival was on average 26.7 months in patients who received Gazyvaro and chlorambucil and 15.2 months in those who received rituximab and chlorambucil. Unknowns relating to treatment benefits The main study with Gazyvaro was carried out in adult patients who had mild or moderate kidney problems and/or other medical conditions besides CLL. The information gained from this study can be applied to all patients with previously untreated CLL and other medical conditions that make them unsuitable for full-dose fludarabine-based therapy. Page 1/10

2 Summary of safety concerns Important identified risks Risk What is known Preventability Infusion-related reactions The majority of patients treated with Gazyvaro have experienced reactions related to infusion of the medicine. These reactions occur mainly during or after the first infusion. Their frequency and severity decrease with later infusions. Reactions reported to date include headache, fever, flushing, chills, feeling sick, shortness of breath, low or high blood pressure, tachycardia (heart beating very fast), vomiting and diarrhoea. The risk of infusion-related reactions can be reduced by the administration of medication to prevent these reactions (corticosteroids, paracetamol, antihistamines). In addition, the first dose of obinutuzumab can be split over two days: 100 mg on day 1 and the remaining dose (900 mg) on day 2. The infusion may be slowed down, or interrupted should severe symptoms occur and appropriate medication given to treat the symptoms. Patients treated with anti-hypertensive medication (drugs that lower blood pressure) may have their medication stopped before and during infusion. Less frequently, some patients may experience wheezing, difficulty breathing, tight chest, throat irritation, throat and airway swelling and irregular heartbeat. Most reactions have been mild to moderate, but some severe and life-threatening reactions have been reported. Tumour lysis syndrome (a complication due to the breakdown of cancer cells) Treatment with Gazyvaro can result in the cancer cells being destroyed very quickly, which can result in adverse effects as the body tries to remove the breakdown products from these cells (potassium, phosphate and uric acid). Drinking plenty of fluids and taking the medicine allopurinol hours prior to infusion of obinutuzumab is recommended for patients with high circulating white blood cell counts, in order to reduce the risk of tumour lysis syndrome. Tumour lysis syndrome may be serious and can lead to Page 2/10

3 Risk What is known Preventability kidney failure. Low levels of platelets (blood cells that help the blood to clot) (thrombocytopenia) Some patients have had a significant reduction in the blood levels of platelets after treatment with Gazyvaro. In most cases this was not serious. However, thrombocytopenia may give rise to haemorrhages (bleeding), which can be fatal. Low platelet levels cannot be prevented. Transfusion of blood products may be required to increase the number of platelets and to reduce the risk of bleeding. Low levels of neutrophils (a type of white blood cell) (neutropenia) Increased rates of neutropenia have been observed in patients treated with obinutuzumab. Low levels of neutrophils may lead to infections. Low neutrophil levels cannot be prevented. Patients who experience neutropenia should be closely monitored until neutrophil levels return to normal. Most cases of neutropenia in obinutuzumab-treated patients were non-serious and of short duration, although serious cases associated with infections, some lifethreatening, have been reported. Low levels of neutrophils which can occur several days after treatment has been started and may persist after treatment discontinuation (late onset/prolonged neutropenia) Neutrophil blood levels may fall more than 28 days after treatment has been completed or low neutrophil levels found during treatment may take a long time to return to normal (longer than one month after treatment stops). The occurrence of late onset or prolonged neutropenia cannot be prevented. This may increase the risk of infections, although most infections seen in Gazyvarotreated patients who experienced delayed or prolonged neutropenia were Page 3/10

4 Risk What is known Preventability mild. Delay in restoring normal blood levels of B-cell lymphocytes (a type of white blood cell) to normal levels (prolonged B-cell depletion) Lowering the level of B-cell lymphocytes is the intended effect of obinutuzumab. The time taken for B-cell lymphocytes to return to normal levels in the body may be very long (i.e., more than one year). Prolonged depletion cannot be prevented, but B-cell levels can be monitored to follow their return to normal. Prolonged depletion of white blood cells could potentially increase the risk of infections, although studies with obinutuzumab have not confirmed this. Infections White blood cells help the body to fight infections, therefore the depletion of B- cells, as well as the neutropenia that can occur after treatment with Gazyvaro, increase the risk of infections. Some infections can be serious or even fatal. Obinutuzumab should not be given to patients with active infections. The risk of infection can be reduced by maintaining a good oral hygiene (with dental assessment before treatment if necessary), as well as by avoiding constipation. Signs or symptoms of infection should receive prompt medical treatment. Return of hepatitis B in patients who have had hepatitis B in the past (hepatitis B reactivation) In patients who have had hepatitis B in the past, treatment with Gazyvaro may increase the risk of the hepatitis B infection coming back. Reactivation of hepatitis B is known to occur in patients who undergo chemotherapy and in patients treated with other anti-cd20 monoclonal antibodies. The chance of developing an active hepatitis B infection is low, but this can sometimes be serious, or even fatal. Hepatitis B virus screening should be performed in all patients before starting treatment with Gazyvaro. Screening should include hepatitis B surface antigen (HBsAg)-status and hepatitis B core antibody (HBcAb)- status. Patients with active hepatitis B disease should not be treated with Gazyvaro. Patients who test positive for hepatitis B should consult liver disease experts before starting treatment and should be monitored and managed to prevent Page 4/10

5 Risk What is known Preventability hepatitis reactivation. A very rare and lifethreatening viral infection called progressive multifocal leukoencephalopathy (PML) PML causes brain damage and is almost always fatal or causes severe disability. This disease can occur in cancer patients even if they do not receive anticancer treatment. PML cannot be prevented, but patients can be monitored to detect the condition. PML has occurred in cancer patients treated with monoclonal antibodies. PML has been reported in patients treated with Gazyvaro. Worsening of heart problems (cardiac disorders) Worsening of existing cardiac conditions has been seen in some patients treated with Gazyvaro, although a direct association with obinutuzumab has not been established. Patients with cardiac disorders should be closely monitored. Patients with known cardiac disorders should be hydrated with caution to prevent a potential fluid overload, and thus minimise the risk of worsening heart problems. Important potential risks Risk What is known Vaccinations may not be effective (impaired immunisation response) The action of Gazyvaro on white blood cells may reduce the effect of vaccination. No vaccination studies have been performed in patients receiving Gazyvaro. Development of antibodies against Gazyvaro Patients may develop antibodies against Gazyvaro that could affect their ability to respond to treatment or might result in adverse events. (immunogenicity) New cancers (second malignancies) Patients treated with Gazyvaro may be at increased risk of developing new cancers because of depletion of their white blood cells. The development of new cancers has been seen in some patients treated with Gazyvaro. However, Page 5/10

6 Risk What is known there are other risk factors for the development of second cancers in CLL patients, including the underlying disease and advanced age (most CLL patients are elderly). Developing a hole or tear in the walls of the gut (gastrointestinal perforation) Patients may be at increased risk of developing gastrointestinal perforation when treated with Gazyvaro. Cases have been reported in non-hodgkin lymphoma patients treated with Gazyvaro. No cases have been seen in CLL patients treated with Gazyvaro to date, but cases have been reported in CLL patients treated with a similar monoclonal antibody. Disorders mediated by the immune system that cause inflammation in the kidneys (immunemediated glomerulonephritis) Kidney problems have been seen in monkeys treated with Gazyvaro. These effects are considered to be specific to animals and have not been observed in humans. Missing information Risk What is known Use in children Gazyvaro has not been studied in children. Use in pregnancy and while breastfeeding Gazyvaro has not been studied in women who are pregnant or breastfeeding. Studies in monkeys have not identified any particular risks for pregnant mothers, although infants were born with low levels of white blood cells. Women who are able to become pregnant should use an effective method of birth control for 18 months after treatment with Gazyvaro. If women do receive treatment with Gazyvaro during pregnancy, infants may be born with low levels of white blood cells. Vaccination of these infants with live vaccines should be delayed until the infant s white blood cell levels return to normal. Because it is possible that Gazyvaro may be excreted in human milk, women should be advised not to breastfeed during treatment with obinutuzumab and for 18 months after stopping treatment. Page 6/10

7 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. The SmPC and the package leaflet are part of the medicine s product information. The product information for Gazyvaro can be found on Gazyvaro 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 Study BO21004: Obinutuzumab + chlorambucil compared to rituximab + chlorambucil or chlorambucil alone in previously untreated CLL patients with comorbidities. Primary objective: to demonstrate clinically relevant statistical superiority in progression-free survival of obinutuzumab + chlorambucil rituximab + chlorambucil, and chlorambucil alone and rituximab and chlorambucil chlorambucil in previously untreated CLL patients with other medical conditions. Infusion-related reactions (confirmation of decrease in infusionrelated reactions since protocol amendment introducing split dosing, slow infusion and reinforcing pre-existing risk minimisation measures) (complete) Prolonged B-cell depletion Immunogenicity Study ongoing Q (Stage 2 analysis CSR) Q (Final CSR) Secondary objective: Immune-mediated glomerulonephritis to evaluate and compare the safety profile of patients. Study BO21005: Obinutuzumab in Primary objective: Thrombocytopenia Study Q Page 7/10

8 Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results combination with CHOP versus rituximab and CHOP in previously untreated patients with CD20-positive DLBCL. to demonstrate superiority in progression-free survival of obinutuzumab + chemotherapy rituximab + chemotherapy in previously untreated diffuse large B-cell lymphoma patients. Late onset and prolonged neutropenia Prolonged B-cell depletion Immunogenicity ongoing Immune-mediated Secondary objective: glomerulonephritis to evaluate and compare the safety profiles of patients treated with the combination of obinutuzumab and CHOP (a chemotherapy treatment) with rituximab and CHOP. Study BO21223: Obinutuzumab plus chemotherapy rituximab plus chemotherapy in previously untreated patients with advanced indolent lymphoma followed by GA101 1 or rituximab maintenance therapy Primary objective: efficacy of obinutuzumab + chemotherapy followed by obinutuzumab maintenance therapy, compared with rituximab + chemotherapy followed by rituximab maintenance therapy in previously Thrombocytopenia Late onset and prolonged neutropenia Prolonged B-cell depletion Immunogenicity Study ongoing Q obinutuzumab Page 8/10

9 Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results in responders. untreated advanced follicular lymphoma. Immune-mediated glomerulonephritis Secondary objective: to evaluate and compare the safety profiles between the two treatment arms. Study MO28543: Obinutuzumab in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL Primary objective: to evaluate the safety and tolerability of obinutuzumab alone or in combination with chemotherapy Infusion-related reactions Study ongoing Q Study GAO4753g: Obinutuzumab in combination with bendamustine bendamustine in patients with rituximab-refractory indolent NHL Primary objective: to evaluate clinical benefit in terms of progression-free survival of obinutuzumab in combination with bendamustine bendamustine alone, in patients with indolent non- Hodgkin lymphoma refractory to prior rituximab-containing therapy. Thrombocytopenia Prolonged B-cell depletion Study Ongoing Q (approx.) Secondary objective: to evaluate and compare the safety profiles of patients treated with Page 9/10

10 Study/activity (including study number) Objectives Safety concerns /efficacy issue addressed Status Planned date for submission of (interim and) final results bendamustine + obinutuzumab and bendamustine alone. Drug Safety Report on haemorrhagic events in the context of thrombocytopenia Evaluation of the incidence, severity and temporal relationship of haemorrhagic (bleeding) events and assessment of relationship with thrombocytopenia Thrombocytopenia In preparation Q (latest) Studies which are a condition of the marketing authorisation None. Summary of changes to the risk management plan over time Not applicable. This summary was last updated in Page 10/10