VI.2 Elements for a public summary VI.2.1 Overview of disease epidemiology Cardiovascular disease (CVD) is responsible for one-third of global deaths and is a leading and increasing contributor to the global disease burden. Cardiovascular diseases are a group of disorders of the heart and blood vessels and they include coronary heart disease disease of the blood vessels supplying the heart muscle. In patients with coronary heart disease and previous heart attacks, the risk of new cardiovascular events is higher than in healthy population. One of the highly prevalent risk factor for CVD is hyperlipidaemia or hyperlipoproteinemia including hypercholesterolemia which is extremely common in the general population. Among the dyslipidaemias hypercholesterolemia is the most important risk for the development of coronary heart disease and the main responsible lipoprotein in coronary atherosclerosis is low density lipoprotein (LDL) which carries the most of plasma cholesterol in the blood. The cholesterol levels in developing countries tend to increase as western dietary habits replace traditional diets. Hypercholesterolemia is more common in men younger than 55 years and in women older than 55 years. In adults, hypercholesterolemia increases with advancing age. Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease. Patients who have one abnormal copy (are heterozygous) of the low-density lipoprotein receptor (LDLR) gene may have premature cardiovascular disease at the age of 30 to 40 years. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, inherited in an autosomal dominant pattern, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births. Sitosterolemia (also known as "Phytosterolemia") is a rare genetic lipid disorder. It is characterized by an excess in absorption and decrease in excretion of plant sterols leading to hypercholesterolemia. The guidelines of the American Heart Association and the NCEP Adult Treatment Panel III (ATP III) define hypercholesterolemia as a blood cholesterol concentration of greater than or equal to 6.2 mmol/l (240 mg/dl). Desirable cholesterol concentrations are less than 5.2 mmol/l (200 mg/dl). VI.2.2 Summary of treatment benefits Based on the available data from clinical studies and clinical experience, Ezetimibe represents an effective drug in the treatment/prevention of Primary Hypercholesterolemia, Homozygous Familial Hypercholesterolemia (HoFH) and Homozygous Sitosterolaemia (phytosterolemia). Ezetimibe has also been proven effective in reducing the risk of cardiovascular events in patients with disease of the blood vessels supplying the heart muscle and a history of previous heart attacks when added to ongoing statin (usual cholesterol lowering) therapy or initiated together with a statin. If administered as indicated in the Summary of Product Characteristics and taking into account the contra-indications, the warnings and precautions, ezetimibe can be considered effective in the approved indications and generally well tolerated.
VI.2.3 Unknowns relating to treatment benefits The benefits of ezetimibe use during pregnancy and lactation as well as use in children less than 10 years of age have not been established yet. VI.2.4 Summary of safety concerns Important identified risks What is known Preventability Muscle disease and abnormal muscle breakdown which can lead to kidney problems (Myopathy/ Rhabdomyolysis) As with other cholesterollowering medicines, a very small number of people have experienced unexplained muscle pain, tenderness, or weakness. This is because on rare occasions, muscle problems, including muscle breakdown resulting in kidney damage, can occur and may become a potentially life-threatening condition. Ezetimibe therapy should be stopped and medical help should be sought immediately if any unusual aches or pains in muscles last longer than expected. Abnormal liver functions When ezetimibe is used with a statin (another class of drugs used to lower cholesterol levels), an elevation in liver enzymes in the blood has been observed. Due to the unknown effects of the increased exposure to ezetimibe, its use in patients with moderate or severe hepatic insufficiency is not recommended. Your doctor should do a blood test before you start taking ezetimibe with a statin. This is to check how well your liver is working. Your doctor may also want you to have blood tests to check how well your liver is working after you start taking Ezetimibe with a statin. Patients who currently have liver problems or whose laboratory blood test results show an abnormal liver function for a longer period without any known reason should not take ezetimibe together with a statin. Hypersensitivity reactions (Allergic reaction) Drug interaction with cyclosporine People taking ezetimibe can experience allergic reactions, including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing. People taking ezetimibe together with cyclosporin (often used in organ transplant patients) can be exposed to higher doses of ezetimibe than usual. Patients who are allergic to ezetimibe or any of the other ingredients of this medicine should be prohibited from using this drug. Patients should tell doctor about all their medical conditions including allergies. is stated in the labelling. Patients should inform their doctor or pharmacist if they are taking, have recently taken or might take any other medicines
What is known Preventability including those obtained without a prescription. In particular, they should tell their doctor if they are taking medicine(s) containing cyclosporine (often used in organ transplant patients). Cyclosporine concentrations should be monitored in patients receiving ezetimibe and cyclosporine. Drug interaction with warfarin, another coumarin anticoagulants, or fluindione Ezetimibe added to anticoagulant therapy may result in higher INR (indicating a higher risk of bleeding). Patients should inform their doctor or pharmacist if they are taking, have recently taken or might take any other medicines including those obtained without a prescription. In particular, they should tell their doctor if they are taking medicine(s) containing active ingredient to prevent blood clots, such as warfarin, phenprocoumon, acenocoumarol or fluindione (anticoagulants). Important potential risks Pancreatitis (Inflammation of the pancreas) What is known (Including reason why it is considered a potential risk) Pancreatitis is the medical term for the inflammation of the pancreas. It can be manifested with a sudden onset accompanied with intensive symptoms called acute pancreatitis or can occur over several years often with moderate and non-specific symptoms (especially in the first period), the latter called as chronic pancreatitis. Acute inflammation of the pancreas is often associated with gallstones. The most common symptoms of pancreatitis are severe upper abdominal burning pain radiating to the back, nausea, and vomiting that is worsened with eating. Acute pancreatitis might be manifested in mild or more severe form with complications leading to a potentially life-threatening condition. After ezetimibe products were put on the market, there were reports about inflammation of the pancreas (pancreatitis) which occurred during treatment with ezetimibe. Patients receiving ezetimibe and their doctors should be aware of the possible risk of pancreatitis. If patients experience symptoms typical for pancreatitis (such as severe abdominal pain which radiates to the back, jaundice, fever, severe nausea and vomiting), they should immediately contact their doctors, as early diagnosis and treatment of this condition is essential for a better outcome.
Cholecystitis/ Cholelithiasis (gallstones or inflammation of the gallbladder) What is known (Including reason why it is considered a potential risk) Gallstones or inflammation of the gallbladder (which may cause abdominal pain, nausea, vomiting) have been reported in general use. Patients are advised to contact their doctor if the experience abdominal pain, nausea, vomiting Missing information Limited exposure in children aged 10 to 17 years (beyond 1 year) and limited exposure in children less than 10 years of age What is known There is limited clinical experience about the use of ezetimibe in adolescent patients (aged 10-17 years old). During the development of this medicine, a study involving about 250 boys and girls of 10 to 17 years of age was carried out, where the patients were treated with ezetimibe and simvastatin (another medicine for the treatment of high blood cholesterol level) together. In this study, there was generally no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. However, the effects of ezetimibe for a longer treatment period (over 33 weeks) on growth and sexual maturation have not been studied. The long-term effectiveness of the ezetimibe therapy regarding its further positive effects for the adulthood in patients below 17 years of age has not been studied. There is limited data on the safe and effective use of ezetimibe in children between 6 and 10 years of age, and there is no available data on use of ezetimibe in children younger than 6 years. During the development of this medicine, the use of ezetimibe (regarding its effectiveness and safety) was studied during a 12-week treatment period in about 140 children of 6 to 10 years of age. However, effects of ezetimibe for treatment periods over 12 weeks have not been studied in this age group and the long-term effectiveness of the ezetimibe therapy regarding its further positive effects for the adulthood in patients below 17 years of age has not been studied. Furthermore, ezetimibe has not been studied in patients younger than 6 years of age. Since there are no sufficient data on the effective and safe use of ezetimibe in children under 10 years of age, the product is not recommended in this age-group. In case ezetimibe therapy would be necessary in this age group, the treatment must be started under the control of a specialist and close follow-up is needed. Do not give this medicine to children and adolescents between 6 and 17 years unless prescribed by a specialist because there are limited data on safety and efficacy. Do not give this medicine to children less than 6 years old because there is no information in this age group.
Use during pregnancy and lactation What is known Since there are no sufficient data on the safe use of the product during human pregnancies (since its use was not examined during human pregnancies), therefore taking ezetimibe is not recommended in women who are actually or might be pregnant. Ezetimibe should be given to pregnant women only if clearly necessary. Simultaneous therapy with ezetimibe and a statin is prohibited during pregnancy, therefore patients should not take ezetimibe with a statin if they are pregnant, are trying to get pregnant or think they may be pregnant. Patients, who get pregnant while taking ezetimibe together with a statin, should stop taking both medicines immediately and contact their doctor. Patients who are pregnant or breast-feeding, or who think they may be pregnant or who are planning to get pregnant, should consult their doctors or pharmacist before starting the treatment with ezetimibe. 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. The SmPC and the package leaflet are part of the medicine s product information. This medicine has no additional risk minimisation measures. VI.2.6 Planned post authorisation development plan Not applicable. VI.2.7 Summary of changes to the risk management plan over time Not applicable.