Elements for a public summary

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1 VI.2 VI.2.1 Elements for a public summary Overview of disease epidemiology Chronic myeloid leukaemia (CML) CML is the most common of the blood cancers. It accounts for 15-20% of all cases of leukemia. Approximately 1-2 people per 100,000 people every year have CML. People are generally between years of age when they are diagnosed. There are slightly more men than women who are diagnosed with CML, and it is slightly more common in Whites and Blacks than in other races (such as Hispanics or Asians).Since 2001, approximately 87 out of 100 people with CML live 8 years since being diagnosed. Patients with CML who do not receive medical treatment generally will die in approximately 4 to 6 years 4. Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ ALL) There are 2 general age groups where people may be diagnosed with Ph+ ALL. Group 1: 2-4 years of age Group 2: more than 50 years of age. For group 1, 4-5 of every 100 children are diagnosed with Ph+ ALL. For group 2, approximately 1 in every 100,000 people are diagnosed with Ph+ ALL. ALL makes up 75% of all leukemias in children below 15 years of age and 12% in adults. The number of boys or girls who have Ph+ ALL is about the same. In adults, more men than women have ALL. Cancer Research UK (CRUK) lists the following risk factors for ALL: radiation exposure (such as x-rays) exposure to benzene (a chemical found in gasoline and sometimes used in lab experiments) smoking and coffee drinking genetic conditions (such as Down s syndrome) past chemotherapy (drugs to treat cancers) being overweight contact with paint having a weak immune system In people with acute lymphoblastic leukemia, Ph+ ALL has the worst prognosis. Long-term survival estimates range from 35% to 40% in children and less than 20% in adults 4. Gastrointestinal Stromal Tumor (GIST) Little information is known on how many people have GIST. One study reported 129 for every one million inhabitants in Sweden with GIST. The number of people who have GIST increases with age. GIST may occur in patients with a family history for GIST or some other genetic conditions. Many patients have surgery to remove the GIST. Approximately 45 people out of 100 will live 5 years. This time period can depend on whether the tumour has spread to other parts of the body. One study showed about 73 people out of 100 lived for a total of 3 years during the years of the study (from 1993 to 2002) 4. Myelodysplastic/myeloproliferative diseases (MDS/MPD) Myelodysplastic disease refers to a group of related disorders in which abnormal blood-forming cells develop in the bone marrow. At first, these cells interfere with the production of normal blood cells. Later, these cells may become cancerous, turning into a form of leukemia. The three main types of MDS/MPD are chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, and atypical chronic myelogenous leukemia 15. MDS are most common in people between the ages of 65 to 70. Only one in five people (20%) with MDS are younger than 50 years of age 2. Some factors increase the risk of developing MDS. One of these is exposure to the chemical substance benzene. More rarely, MDS is caused by radiotherapy or chemotherapy. This is called secondary or treatment-related MDS 2.

2 MPD are rare conditions that usually develop slowly over a number of years. Most people diagnosed are over 60 years of age 3. Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Over time, these high numbers of eosinophils enter various tissues, causing inflammation and eventually damaging the body organs, most commonly targeting the skin, lung, heart, blood and nervous system. HES can become life-threatening if not treated. HES can affect anyone, but it occurs more often in men, usually between 20 and 50 years of age. Symptoms of HES vary, depending on what part of the body is affected. Skin symptoms include, among others, itching and rashes. If the lungs are affected, the person may be short of breath and cough 13. Dermatofibrosarcoma protuberans (DFSP) DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. It is estimated that one in 10,000 people are affected by DFSP and that every year one in 200,000 people is diagnosed with this disease. DFSP can occur, sporadically, at any age, including infancy and childhood, but it usually affects people between 10 and 50 years of age 18. Most DFSP (85-90%) are benign (low grade), while the rest is classified as the aggressive so-called high grade fibrosarcomatous type. The lesions typically present as a callous-like pink or violet-red plaque or nodular mass on the trunk, limbs, or head and neck region. Growth tends to be slow with local infiltration into deeper tissues and a propensity for local recurrence after excision. However, metastases are rare. VI.2.2 Summary of treatment benefits The active substance in imatinib, is a protein-tyrosine-kinase inhibitor. This means that it blocks some specific enzymes known as tyrosine kinases. These enzymes can be found in some receptors on the surface of cancer cells, including the receptors that are involved in stimulating the cells to divide uncontrollably. By blocking these receptors, imatinib helps to control cell division 4. Imatinib was more effective than the comparator medicines. In patients with CML, the cancer had got worse in 16% of the patients taking imatinib after five years, compared with 28% of those taking interferon alpha plus cytarabine. Imatinib was also better than standard chemotherapy in patients with ALL. In patients with GIST that had been removed with surgery, patients taking imatinib lived for longer than those taking placebo without their cancer coming back. In the non-comparative studies of CML, ALL and GIST, between 26 and 96% of patients showed a response to imatinib. Due to their rarity, limited data were available for the other diseases, but around two thirds of the patients showed at least a partial response to imatinib 4. VI.2.3 Unknowns relating to treatment benefits Special populations Children Imatinib is also a treatment for children with CML. However, there is no experience in children with CML below two years of age. Elderly patients (age 65 and older) Imatinib behaviour in the body (pharmacokinetics) has not been specifically studied in elderly patients, but older age does not seem to cause big differences in the way the drug acts within the body. No specific dose recommendation is necessary for older patients. However, elderly patients treated with imatinib might experience water retention more often than younger patients. Patients with liver problems The liver is the main organ responsible for inactivating (metabolizing) imatinib after a certain amount of time that it is in the body. If the liver does not work properly, it can be that patients taking imatinib have in their body an amount of active medicine higher than expected, which could lead to increased side effects.

3 Patients with kidney problems Patient with kidney problems might react too strongly to imatinib; therefore they might need lower dosages of this medicine. Long-term effects The effects on growth of the use of imatinib for longer periods in children are not known. There have been cases of children and pre-adolescents who received imatinib and had growth retardation. VI.2.4 Summary of safety concerns Table 3 summarizes what is known about each important identified risk associated with the use of imatinib and its preventability. Current knowledge on important potential risks and important missing information associated with the use of imatinib is summarized in Table 4 and Table, respectively. Table 3. Current knowledge about important identified risks related to the use of imatinib, and their preventability. Risk What is known Preventability Heart failure (cardiac failure) Congestive heart failure is a serious event which occurs in less than one in 100 patients Heart arrest and heart attack might also occur, each in less than one in 1,000 patients treated with imatinib. In some cases these events can be fatal. Bleeding in the stomach/intestine, or brain (central nervous system and gastrointestinal haemorrhages) Gastrointestinal obstruction, perforation, or ulceration Growth retardation in children Unexpected bleeding is a common side effect of imatinib, occurring in up to one in 10 patients. Bleeding in the stomach/intestine, and bleeding in the brain are serious events occurring in less than one in 100 patients treated with imatinib. Some patients treated with imatinib (less than one in 1,000 patients) might experience an increase in the pressure in the head. Constipation is a common nonserious side effect of imatinib, occurring in up to one in 10 patients. Other gastrointestinal side effects, such as stomach damage (gastric ulcer), obstruction of the intestine (ileus, intestinal obstruction), or stomach/intestine perforation (gastrointestinal perforation) are serious events, and occur with variable frequency. It happened that some children treated with imatinib had a growth slower than normal. The doctor should take particular care of all patients receiving imatinib who are at risk of cardiac events. Doctors should monitor the growth of children and adolescents at regular visits, and act accordingly.

4 Liver damage (Hepatotoxicity) Low phosphate levels in the blood (Hypophosphataemia) Low levels of thyroid hormones (Hypothyroidism) Inability to produce all blood cells (myelosuppression) Oedema and water retention (fluid retention) Liver damage can occur with imatinib treatment: increase in liver values happens in up to one in 10 patients; yellow appearance of the patient (jaundice), inflammation of the liver (hepatitis), and excessive bilirubin in the blood (hyperbilirubinaemia) may affect up to one in 100 patients; liver failure (hepatic failure) and liver death (hepatic necrosis) may affect up to one in 1,000 patients Most of these events are serious, and in some cases they can even be fatal. The use of imatinib together with other medicines, for instance chemotherapy drugs, might increase the incidence of liver damage. This non-serious event occurs in less than one in 100 patients A few patients that had the thyroid removed, developed hypothyroidism (low levels of thyroid hormones) when taking imatinib at the same time as the medicine levothyroxine. It is however unclear why/how this might happen. The inability to produce all blood cells (bone marrow depression) is a serious event occurring in less than one in 100 patients Cytopenias (low numbers of any of the cellular elements of the blood) might also occur in patients treated with imatinib, with variable frequency and degree of seriousness. Oedema and water retention may affect up to one in 10 or more than one in 10 patients treated with imatinib, especially older patients, and patients with heart problems. These events are rarely severe and usually manageable, but they can sometimes be serious and lifethreatening. One patient with liquid in the lungs (pleural effusion), and heart and kidney failure, died. The risk of liver damage might be reduced if imatinib is not taken together with other medicines, such as chemotherapy drugs. The doctor will evaluate whether this is possible. In addition, the doctor should regularly perform blood tests that indicate whether or not the liver is functioning properly. Doctors are informed about this risk. Yes, the doctor might decide not to prescribe imatinib and levothyroxine at the same time, if alternatives are available. The doctor will evaluate whether this is possible. Not preventable. However, if severe cytopenias occur, the doctor might decide to stop imatinib treatment or to change the dosage. The doctor (or nurse) should regularly weigh the patient. The doctor should also carefully decide whether older patients or patients with heart problems should take imatinib or not. Oedemas may be managed with diuretics (medicines that help the body reduce the amount of retained water), other supportive measures, or by reducing the dose of imatinib.

5 Ovarian bleeding (ovarian haemorrhage) and bleeding ovarian cyst (haemorrhagic ovarian cyst) Acute kidney failure (renal failure acute) Muscle damage (rhabdomyolysis) and muscle disease (myopathy) Severe respiratory adverse reactions Skin rashes and severe cutaneous reactions Tumour lysis syndrome These are serious events which occur each in less than one in 1,000 patients treated with imatinib. It is a serious event which occurs in less than one in 100 patients In some cases it can be fatal. These serious events occur in less than one in 1,000 patients Infection of the upper airways (upper respiratory tract infection) is a serious event which may affect up to one in 100 patients treated with imatinib. Formation of fibrous tissue in the lungs (pulmonary fibrosis) and increased blood pressure in the lungs (pulmonary hypertension) are serious events which occur each in less than one in 1,000 imatinib-treated patients. Acute respiratory failure is a serious event occurring with unknown frequency. Some patients with acute respiratory failure and other serious concomitant conditions died. These skin-related events, some of which are serious, occur with variable frequency in patients Tumour lysis syndrome is a serious condition that can originate from the presence of dead tumour cells in the blood following tumour treatment. Tumour lysis syndrome can manifest with nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort, and is associated with abnormal laboratory test results (e.g. high potassium, uric acid and phosphorous levels and low calcium levels in the blood). It may affect up to one in 1,000 patients The doctor should take particular care of patients treated with imatinib, if they are already at risk for kidney problems. If the patient is dehydrated or has high uric acid levels in the blood, the doctor should correct these conditions before initiating imatinib treatment.

6 Table 4. Current knowledge about important potential risks related to the use of imatinib. Risk Widespread blood cloths in the blood vessels (disseminated intravascular coagulation) Low glucose levels in the blood (hypoglycaemia) Possibility of a second malignant disease Suicidality Use during pregnancy and consequences on the baby What is known (Including reason why it is considered a potential risk) There have been a few cases in which patients treated with imatinib developed widespread blood cloths in the blood vessels. It is however unclear whether this was due to the drug or to the disease. There have been a few cases in which patients treated with imatinib developed low glucose levels in the blood. It is however unclear why/how this might happen. In laboratory animals it was noted that treatment with imatinib can cause the development of other malignant diseases (cancers). It is however unclear how and if this might happen also in patients. Although some patients who received treatment with imatinib did attempt or commit suicide, it is not clear whether these events are indeed related to imatinib. Little information is available regarding pregnant women taking imatinib. Therefore, it is not clear whether taking this medicine during pregnancy might be dangerous for the unborn child or not. However, studies in laboratory animals showed that imatinib might be toxic for the foetus. If the patient is pregnant, thinks she may be pregnant or is planning to have a baby, she should ask her doctor for advice before taking imatinib. Imatinib is not recommended during pregnancy unless clearly necessary as it may harm the baby. Women who might become pregnant are advised to use effective contraception during treatment. Only two women breast-feeding while taking imatinib have been studied. Although only a small amount of imatinib can go into the breast milk, it is not known whether this amount can be dangerous for the baby. Therefore women taking imatinib should not breastfeed. Table 5. Current knowledge about important identified interactions related to the use of imatinib and their preventability. Risk What is known Preventability (drugs eliminated by CYP3A4) (strong CYP3A4 inducers) (strong CYP3A4 inhibitors) Imatinib can interfere with the effect of some medicines when taken together. It may increase their effect, possibly leading to increased risk or severity of side effects. Some medicines can interfere with the effect of imatinib when taken together. They may decrease the effect of imatinib, making it less effective. Some medicines can interfere with the effect of imatinib when taken together. They may increase the effect of imatinib, leading to increased risk or severity of side effects. The doctor should carefully decide whether to prescribe imatinib together with drugs that may have their effect potentiated by imatinib. The doctor should avoid prescribing imatinib together with drugs that may reduce its effect. The doctor should carefully decide whether to prescribe imatinib together with drugs that may potentiate its effect.

7 Table 6. Current knowledge about important potential interactions related to the use of Risk Interaction with the medicine acetaminophen (also called paracetamol) (Acetaminophen/paracetamol) (Drugs eliminated by CYP2C9, CYP2C19 and CYP2D6) What is known (Including reason why it is considered a potential risk) Laboratory studies showed that imatinib might interfere with paracetamol medicinal action, although this has not been confirmed in animal studies. One person, who was using imatinib and high dosages of paracetamol at the same time, died after developing a severe liver problem. Imatinib can interfere with the effect of some medicines when taken together. It may increase their effect, possibly leading to increased risk or severity of side effects. Table 7. Current knowledge about important missing information on the use of imatinib. Risk Use in elderly patients (age 65 and older) Use in children younger than two years of age Use in children: long-term effects Use in patients with liver problems Use in patients with kidney problems What is known (Including reason why it is considered a potential risk) Imatinib behaviour in the body (pharmacokinetics) has not been specifically studied in elderly patients, but older age does not seem to cause big differences in the way the drug acts within the body. No specific dose recommendation is necessary for older patients. However, elderly patients treated with imatinib might experience water retention more often than younger patients. Imatinib is also a treatment for children with CML. However, there is no experience in children with CML below two years of age. There have been cases of children and pre-adolescents who received imatinib and had growth retardation. The effects on growth of the use of imatinib for longer periods in children are not known. The liver is the main organ responsible for inactivating (metabolizing) imatinib after a certain amount of time that it is in the body. If the liver does not work properly, it can be that patients taking imatinib have in their body an amount of active medicine higher than expected, which could lead to increased side effects. Patient with kidney problems might react too strongly to imatinib; therefore they might need lower dosages of this medicine. VI.2.5 Summary of additional risk minimisation measures by safety concern No additional risk minimisation measures have been proposed. VI.2.6 Planned post authorisation development plan (if applicable) No post-authorization development is planned. VI.2.7 Summary of changes to the risk management plan over time Since this is the first RMP for the Applicant s imatinib film-coated tablets, this section is not applicable.