Summary of the risk management plan (RMP) for Spectrila (asparaginase)

Transcription

1 EMA/829066/2015 Summary of the risk management plan (RMP) for Spectrila (asparaginase) This is a summary of the risk management plan (RMP) for Spectrila, which details the measures to be taken in order to ensure that Spectrila 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 Spectrila, which can be found on Spectrila s EPAR page. Overview of disease epidemiology Spectrila is a medicine for treating patients with acute lymphoblastic leukaemia (ALL), a cancer of white blood cells called lymphoblasts. ALL is more common in children than in adults. About 1 in 100,000 adult persons per year gets this disease. In children this rate is between 2 and 4 per 100,000 persons per year. The average age of children with ALL is 4.9 years. Slightly more boys than girls are affected. In adults, half the cases are in patients under the age of 50, and ALL is rare over the age of 70. Summary of treatment benefits In a main study in 199 children with ALL, Spectrila was as effective as another asparaginase medicine (both used in combination with other medicines) in reducing blood asparagine: 95% of patients treated with Spectrila and 94% of those treated with the other medicine containing asparaginase had complete depletion (reduction) of blood asparagine. Unknowns relating to treatment benefits Asparaginase, the active substance in Spectrila, has been in clinical use for more than 2 decades. Spectrila has been shown to be as effective and safe as a reference asparaginase preparation. Summary of safety concerns Important identified risks Risk What is known Preventability Infections (including opportunistic and fungal infections) Since asparaginase has immunosuppressive activity (i.e. it reduces the activity of the immune system), infections may occur during treatment with asparaginase medicines. Monitoring of early symptoms like fever is required to start effective treatment in time. Preventive treatment with antibiotics in case of e.g. very low levels of white blood cells. Page 1/7

2 Severe hypersensitivity (allergic) reactions Decreased asparaginase activity Decrease in blood clotting factors (coagulation factor deficiencies Bleeding (haemorrhage) Blood clots (thromboembolic events) Asparaginase is a foreign protein and may therefore cause allergic reactions. Allergic reactions observed in clinical studies were usually mild to moderate and rarely severe. Patients usually recover without further complications. Antibodies may develop against Spectrila and reduce its activity. This can occur without an allergic reaction. Decreases in blood clotting factors are observed in most patients during treatment with asparaginase. Bleeding, most often nose bleeding, bruising and petechiae (pinpoint flat round red spots under the skin surface) have been reported commonly in patients receiving asparaginase. All patients who received Spectrila and experienced bleeding recovered without further complications. Bleeding is also a commonly observed symptom of the underlying disease because of impaired bone marrow function. Blood clots are a known complication of leukaemia and of several agents used to treat the condition like asparaginase. They have been reported commonly with Spectrila and affect predominantly the veins of Which patient will experience an allergic reaction is unknown. Therefore, monitoring of early symptoms like rash, flushing, swelling of the face and throat, difficulty in breathing, hives (an itchy skin rash) or dizziness, is required to start effective treatment in time. It is not possible to predict which patient will develop antibodies against asparaginase. Regular monitoring of asparaginase blood levels allows early detection of decreased Spectrila activity. Blood clotting values should be monitored before and regularly throughout treatment. Patients with very low levels of these blood clotting factors sometimes receive blood preparations containing these clotting factors intravenously Treatment with asparaginase should be interrupted if patients develop coagulation disorders. Blood clotting values should be monitored before and regularly throughout treatment. Treatment with asparaginase should be interrupted if patients develop coagulation disorder. Blood clotting values should be monitored before and regularly throughout treatment. Page 2/7

3 the limbs (leading to a painful swelling of the limbs [deep vein thrombosis]) or specific veins draining blood from the brain (leading to neurological symptoms such as headache or seizures). Liver toxicity Inflammation of the pancreas (pancreatitis) Nerve disorders (neurotoxicity) Most frequently observed liver disorders during asparaginase treatment are mild to moderate changes in liver parameters, e.g. bilirubin and transaminases, which usually resolve without further complications after the end of treatment. Severe liver disorders requiring prolonged hospital treatment are rare. Pancreatitis (with sudden onset) causing severe pain in the abdomen and back has been observed in less than 1 in 10 patients during treatment with other asparaginase preparations, An increase of serum levels of amylase and lipase (two enzymes produced by the pancreas) may indicate development of pancreatitis in some but not all patients. Most patients usually recover without further complications, however in a few cases, so-called pseudocysts develop in the pancreas which may require surgical treatment. Deaths have been observed very rarely. Most frequently reported nerve disorders include nervousness (agitation), dizziness, somnolence (sleepiness), headache, and changes in the electroencephalogram (a graph showing the electrical activity of your brain). Seizures, severe impairment of consciousness, including coma, and stroke were observed in up to 1 in 1,000 Liver laboratory values such as transaminases and bilirubin levels should be monitored before and regularly throughout therapy. Treatment with Spectrila should be interrupted if patients develop severe liver impairment. Patient who have or have ever had pancreatitis must not receive Spectrila. Several factors may contribute to the development of neurological disorders, e.g. the underlying disease itself, treatment with other medicines, blockage of blood vessels in the brain, and some metabolic disorders. Discontinuation or dose reduction of concomitantly administered immunosuppressive medicines may be necessary. Expert advice should be Page 3/7

4 people. sought. High blood sugar (glucose) levels (hyperglycaemia) Changes in blood fats Increased ammonia levels in blood (hyperammonaemia) Embryotoxic and teratogenic effects (malformations of an embryo or fetus) Interaction with High blood sugar levels have been observed in more than 1 patient in 10 during treatment with Spectrila. This is usually mild and transient, and generally resolves after giving insulin. Hospitalisation is usually not required and no long-term complications have been reported so far. Severe complications of hyperglycaemia (diabetic ketoacidosis) have been reported rarely. An increase in blood fat levels (triglycerides and cholesterol) has been observed in more than 1 patient in 10 during clinical studies conducted with Spectrila. These levels usually return to normal within a few days after stopping Spectrila treatment and only rarely require treatment. An increase of blood ammonia levels has been observed in patients treated with Spectrila, especially in patients with severe liver impairment. This only rarely causes clinical symptoms such as prolonged vomiting. Very rarely it may result in abnormal brain function such as seizures and coma. Studies with Spectrila in mice, rats, chicken and rabbits have shown malformations of embryos or fetuses. The potential risk for humans after treatment with Spectrila as a single treatment is unknown. Combined use of Spectrila and methotrexate may alter the Patients with pre-existing risk factors like diabetes mellitus, obesity, and concomitant treatment with glucocorticoids (cortisone and its analogues) may be at risk of developing high blood sugar levels. Serum and urine glucose levels should be regularly monitored and managed as clinically indicated. No preventive measures exist. Patients with severe liver impairment should not receive asparaginase. Spectrila should not be used during pregnancy. Women should use effective contraception during treatment and up to three months thereafter. Men should use effective contraceptive measures while receiving asparaginase. Treating physicians need to be aware of this schedule-dependent interaction Page 4/7

5 methotrexate Interaction with cytarabine Interaction with glucocorticoids efficacy of methotrexate in different ways depending on which substance is given first. When Spectrila is given first the efficacy of methotrexate is reduced. Conversely, when Spectrila is given after methotrexate it may increase the efficacy of methotrexate. Combined use of Spectrila and cytarabine may alter the efficacy of cytarabine in different ways depending on which substance is given first. When Spectrila is given first the efficacy of cytarabine is reduced. Conversely, when Spectrila is given after cytarabine it may increase the efficacy of cytarabine. The use of glucocorticoids (antiinflammation medicines) at the same time as Spectrila may alter some blood clotting values (fibrinogen, antithrombin III). Furthermore, investigations in mice have shown that these medicines may increase the risk of bone damage (osteonecrosis). when both substances are given concomitantly. Spectrila should always be given after methotrexate. Treating physicians need to be aware of this schedule-dependent interaction when both substances are given concomitantly. Spectrila should always be given after cytarabine. Caution is needed when Spectrila is given with glucocorticoids. Blood clotting values should be monitored regularly throughout treatment.. Important potential risks Risk Reversible posterior leukoencephalopathy syndrome (RPLS) Tumour lysis syndrome (TLS) What is known Patients treated with asparaginase-containing treatment may be at an increased risk of developing a syndrome known as RPLS. Symptoms of RPLS include raised blood pressure, seizures, headaches, changes in mental state and acute visual impairment. Although the condition is reversible, complications, such as bleeding in the brain and stroke, may occur. Discontinuation or dose reduction of concomitantly administered immunosuppressive medicines may be necessary. Expert advice should be sought. During treatment with asparaginase, large amounts of tumour cells can be destroyed in a short time. This could potentially lead to kidney failure; however, this has not yet been seen in clinical practice. Page 5/7

6 Risk Off-label (unauthorised) use via injection into a muscle with vincristine with anticoagulants (used to prevent blood clots) with other medicines where impaired liver metabolism could increase toxicity with live vaccines What is known Although some other asparaginase products are authorised for use by injection into a muscle, Spectrila has only been investigated (and approved) for infusion into a vein. Vincristine (another chemotherapy medicine that is frequently used in patients with leukaemia) is often co-administered with Spectrila. There may potentially be an increase in toxicity when both agents are used together; however, this has not yet been proven in clinical practice. The use of Spectrila can lead to a change in blood coagulation factors. This can promote tendency to either bleeding or blood clotting. Caution is therefore needed when anticoagulants are given at the same time. Spectrila may increase the side effects of other medicines through its effect on liver function. Therefore, caution should be exercised in patients receiving other medicines broken down by the liver. Concomitant vaccination with vaccines containing live organisms may increase the risk of serious infection. Immunisation with live vaccines should therefore take place three months after completion of the cancer treatment at the earliest. Missing information Risk Safety in patients above 65 years of age What is known Experience with asparaginase treatment in patients older than 65 years of age is limited. 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 Spectrila can be found on Spectrila s EPAR page. Page 6/7

7 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 Clinical phase IV study MC- Spectrila.1/ALL Assessment of pharmacokinetics, pharmacodynamics, safety and immunogenicity of Spectrila after repeated-dose treatment of patients with newly diagnosed ALL. Efficacy and safety of Spectrila in adult patients Planned Interim reports will be provided in the RMP updates and PSURs, together with analyses of spontaneous reports from adults treated with Spectrila in other studies. Final report will be submitted approximately 35 months after the granting Marketing Authorisation for Spectrila Studies which are a condition of the marketing authorisation The above study is not a condition of the marketing authorisation. Summary of changes to the risk management plan over time Not applicable. This summary was last updated in Page 7/7