VI.2 VI.2.1 Elements for a Public Summary Overview of disease epidemiology Acute myeloid leukemia (AML) Acute myeloid leukemia (AML) is a type of cancer characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. The symptoms of AML include fatigue, shortness of breath, easy bruising and bleeding, and increased risk of infection. As an acute leukemia, AML progresses rapidly and is typically fatal within weeks or months if left untreated. AML is the most common acute leukemia affecting adults, and its incidence increases with age. 1 PhV-20160316 Page 60/100
Acute Myeloid Leukemia (AML) is a rare malignancy with 13,000 new cases diagnosed in the US each year. The majority patients die from their disease with an estimated 9,000 deaths annually. 1 VI.2.2 Summary of treatment benefits Acute myeloid leukaemia (AML) A study was conducted with high-dose cytarabine (HiDAC) monotherapy compared to intermediate- or high-dose cytarabine combinations in the treatment of acute myeloid leukaemia (AML) A median follow-up of 5 years showed that no significant differences were noted between the intermediate-dose group and the high-dose group with respect to complete remission rates (80% and 82%, respectively), probability of relapse, event-free survival at 5 years (34% and 35%), or overall survival (40% and 42%). High-dose cytarabine provided no clear advantage in any prognostic subgroup. 1 Acute lymphoblastic leukemia (ALL) has demonstrated efficacy in combination with other chemotherapeutic agents as consolidation therapy of acute lymphoblastic leukemia (ALL). In a Southwest Oncology Group study (n=168), the consolidation phase consisted of 3 cycles of cytarabine (continuous infusion of 200 mg/m2 for 5 days) and methotrexate alternating with 3 cycles of cytarabine (150 mg/m2 IV every 12 hours for 6 days) and thioguanine. 1 VI.2.3 Unknowns relating to treatment benefits Based on the currently available data, no gaps in knowledge about efficacy in the target population were identified, that would warrant post-authorisation efficacy studies. Furthermore, there is no evidence to suggest that treatment results would be different in any subgroup of the target population, taking into account factors such as age, sex, race or organ impairment. VI.2.4 Summary of safety concerns Important identified risks Risk What is known Preventability A significant reduction of blood cells production in the bone marrow (myelosuppression) strongly reduces blood cell production in the bone marrow. This can make patients more prone to infections or bleeding. The blood cell numbers can continue to fall for up to a week after stopping treatment. Yes, the doctor will perform blood tests regularly and examine the bone marrow if required. Increased possibility of developing infections (Increased susceptibility to infections) Breaking of the tumour (Tumour lysis syndrome) reduces the effectiveness of the immune system and infections may appear. These infections may be mild, but can be severe and at times fatal. The breaking of the tumour may lead to high levels of uric acid (showing that the cancer cells are destroyed) in the blood (hyperuricaemia) Yes, the doctor will perform blood test regularly. Yes, the doctor will decide the need to take any medicine to control this. PhV-20160316 Page 61/100
Risk What is known Preventability during treatment. Damage to the central nervous system with high dose cytarabine (Central nerve system toxicity with high dose cytarabine) Lung toxicity with high dose cytarabine (Pulmonary toxicity (Pulmonary oedema, adult respiratory distress syndrome) ) Abdomen and intestine toxicity (Gastrointestinal toxicity) Liver toxicity (Hepatic toxicity) Serious and sometimes lifethreatening side effects can occur in the central nervous system: burning pain of palms and soles, neural toxicity, neuritis.. In higher dose therapy, patients may develop personality changes, changed alertness, difficulty in speaking, problems of coordination, tremor, nystagmus, confusion, sleepiness... These symptoms are usually reversible. Serious and sometimes lifethreatening side effects can occur in the lungs. The following side effects may occur: clinical signs of pulmonary oedema / Acute Respiratory Distress Syndrome (ARDS): Sudden, distressing breathing difficulties and water in the lungs. These are more likely to develop with high dose therapy. may cause severe pain in the abdomen, stomach ache or inflammation of the inner lining of the stomach. Especially during treatment with high doses of cytarabine, more severe reactions may appear in addition to common symptoms. During cytarabine treatment liver function should be monitored by using blood tests. Also, if the liver is not working well before treatment, cytarabine should be given only with utmost care. Some of the side effects that can occur when using cytarabine are: increased enzyme levels, impaired liver function, liver abscess. These symp- PhV-20160316 Page 62/100
Risk What is known Preventability toms are usually reversible. Tingling, weakness or pain in hands or feet (Peripheral motor and sensory neuropathies) Headache, paralysis, coma and stroke like episodes (neurologic reactions) - cytarabine in combination with methotrexate Inflammation of the pancreas (pancreatitis) When using high dose cytarabine, damage to the nerves of the hand and feet may appear. This is usually reversible. should not be used in case of increasing difficulties in body coordination after radiation treatment with another anticancer drug such as methotrexate. Paralysis of the legs and lower body can occur when cytarabine is given into the space surrounding the spinal cord, therefore this method of administration is not recommended. A side effect of cytarabine is inflammation of the pancreas. This may appear after therapy with high doses. Yes, by avoiding using cytarabine in combination with methotrexate or other anticancer drugs and also by avoiding the administration of cytarabine into the space surrounding the spinal cord. Missing information Risk Use during breastfeeding (Use in lactating women) What is known The safety of cytarabine for use during breast-feeding is not established. 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 cytarabine. PhV-20160316 Page 63/100
VI.2.7 Summary of changes to the Risk Management Plan over time Version Date Safety Concerns Comment 1.0 25-08-2015 Important identified risks: NA first version Myelosuppression Hyperuricaemia Neurotoxicity Pulmonary toxicity (Ara-C) syndrome Use in pregnancy Important potential risks Reproductive toxicity Missing information Use in infants 2.0 27-05-2016 Important identified risks: The RMP was updated Myelosuppression in relation to Increased susceptibility to infections report and in order Day 70 Assesment Tumour lysis syndrome to harmonise the safety concerns with the Originator s list Central nerve system of safety concerns. toxicity with high dose cytarabine* Pulmonary toxicity (Pulmonary oedema, adult respiratory distress syndrome) with high dose cytarabine Gastrointestinal toxicity Hepatic toxicity with high dose cytarabine Peripheral motor and sensory neuropathies Neurologic reactions (headache, paralysis, coma and stroke like episodes) cytarabine in combination with methotrexate Pancreatitis Important potential risks Not applicable Missing information Use in lactating wom- PhV-20160316 Page 64/100
Version Date Safety Concerns Comment en PhV-20160316 Page 65/100