Elements for a public summary

Transcription

1 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. VI.2.2 Summary of treatment benefits Based on the available data from clinical studies and clinical experience of several years, ezetimibe/simvastatin represents an effective drug in the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia, Homozygous Familial Hypercholesterolaemia (HoFH) and prevention of cardiovascular events. If administered as indicated in the Summary of Product Characteristics and taking into account the contraindications, the warnings and precautions, ezetimibe/simvastatin can be considered effective in the approved indications and generally well tolerated. VI.2.3 Unknowns relating to treatment benefits There is limited clinical trial experience in children aged and no clinical trial experience in children less than 10 years of age. Ezetimibe\simvastatin is not recommended for children under age 10. VI.2.4 Summary of safety concerns Important identified risks Risk What is known Preventability Muscle breakdown resulting in kidney On rare occasions, ezetimibe/simvastatin can cause muscle problems that can be Patients are advised to contact their doctor immediately if they Part V I: Summary of the risk management plan by product Page 29

2 Risk What is known Preventability damage (Myopathy/ Rhabdomyolysis) serious, including muscle breakdown resulting in kidney damage; and very rare deaths have occurred. The risk of muscle breakdown is greater at higher doses of ezetimibe/simvastatin, particularly the 10/80-mg dose. The risk of muscle breakdown is also greater in certain patients. Patients should talk with their doctor if any of the following applies: experience unexplained muscle pain, tenderness, or weakness. Also, patients are advised to tell their doctor or pharmacist if they have a muscle weakness that is constant. Additional tests and medicines may be needed to diagnose and treat this. they have kidney problems they have thyroid problems they are 65 years or older they are female they have ever had muscle problems during treatment with cholesterol lowering medicines called statins (like simvastatin, atorvastatin, and rosuvastatin) or fibrates (like gemfibrozil and bezafibrate) they or their close family members have a hereditary muscle disorder Abnormal liver functions Also, interactions with different medicines can cause the body to be susceptible to muscle breakdown while taking simvastatin. Those drugs include: ciclosporin, itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprivir, telaprevir, danazol, gemfibrozil, fibrates, lipid-lowering doses ( 1 g/day) of niacin, amiodarone, amlodipine, verapamil, inhibitors of BCRP (e.g., elbasvir and grazoprevir), diltiazem, fusidic acid, lomitapide, nefazodone, and medicinal products containing cobicistat. Grapefruit juice contains one or more components that alter the metabolism of some medications, including ezetimibe/simvastatin. Consuming grapefruit juice should be avoided as it may increase your risk of muscle problems. The following common side effects were reported (may affect up to 1 in 10 people): elevations in laboratory blood tests of liver (transaminases) and/or muscle (CK) function Patients are advised to talk to their doctor or pharmacist before taking ezetimibe/simvastatine if they currently have liver problems or if they drink large amounts of Part V I: Summary of the risk management plan by product Page 30

3 Risk What is known Preventability alcohol. Doctor should do a blood test before their patients start taking ezetimibe/simvastatine and if they have any symptoms of liver problems while they are taking ezetimibe/simvastatin. This is to check how well their liver is working. Hypersensitivity reactions Drug interaction with warfarin, another coumarin anticoagulant, or fluindione Drug interaction with cyclosporine The following side effects have been reported in people taking either ezetimibe/simvastatine or medicines containing the active ingredients ezetimibe or simvastatin: a hypersensitivity reaction including some of the following: hypersensitivity (allergic reactions including swelling of the face, lips, tongue and/or throat which may cause difficulty in breathing or swallowing and requires treatment immediately, pain or inflammation of the joints, inflammation of blood vessels, unusual bruising, skin eruptions and swelling, hives, skin sensitivity to the sun, fever, flushing, shortness of breath and feeling unwell, lupus-like disease picture (including rash, joint disorders, and effects on white blood cells)) The risk of bleeding and bleeding-related events is increased in people taking either ezetimibe/simvastatine or medicines containing the active ingredients ezetimibe or simvastatin alongside warfarin, another coumarin anticoagulant, or fluindione. Taking ezetimibe/simvastatin with ciclosporin (often used in organ transplant patients) can increase the risk of muscle problems. Patients are advised not to take ezetimibe/simvastatine if they are allergic to ezetimibe, simvastatin or any of the other ingredients of this medicine. Patients are advised to tell their doctor or pharmacist if they are taking, have recently taken or might take any other medicines. Taking ezetimibe/simvastatine with warfarin, another coumarin anticoagulant, or fluindione can increase the risk of bleeding and muscle problems. Patients are advised to tell their doctor or pharmacist if they are taking, have recently taken or might take any other medicines. Taking ezetimibe/simvastatine with cyclosporine can increase the risk of muscle problems. Part V I: Summary of the risk management plan by product Page 31

4 Important potential risks Risk Inflammation of the pancreas (Pancreatitis) Gallstones or inflammation of the gallbladder (Cholecystitis/Cholel ithiasis) Thickening of the supporting tissues between the air sacs of the lungs (Interstitial Lung disease) Allergy to statins (Simvastatin Hypersensitivity Syndrome) Significant increase in blood sugar levels (New onset diabetes/impaired glucose metabolism) Brain blood vessel burst or a weakened blood vessel leak (Haemorrhagic stroke) What is known (Including reason why it is considered a potential risk) Inflammation of the pancreas often with severe abdominal pain has been reported in people taking either ezetimibe/simvastatin or medicines containing the active ingredients ezetimibe or simvastatin. Inflammation of the liver with the following symptoms: yellowing of the skin and eyes, itching, dark coloured urine or pale coloured stool, feeling tired or weak, loss of appetite; liver failure; gallstones or inflammation of the gallbladder (which may cause abdominal pain, nausea, vomiting) have been reported in people taking either ezetimibe/simvastatin or medicines containing the active ingredients ezetimibe or simvastatin. Breathing problems including persistent cough and/or shortness of breath or fever have been reported in people taking either ezetimibe/simvastatin or medicines containing the active ingredients ezetimibe or simvastatin. For patients who had any previous hypersensitivity reactions to any statin and are fully justified and in need of a statin, the physician may switch from one statin to another, monitor the patient closely, according to his own clinical judgement. Diabetes has been reported in people taking statins. Diabetes is more likely to occur if patients have high levels of sugars and fats in their blood, are overweight and have high blood pressure. Ezetimibe/simvastatine has shown significant benefit for reduction of stroke taken as a whole. However, in clinical studies there was a small and insignificant increase in the risk of a specific subset of stroke (haemorrhagic stroke (weakened blood vessel leak)). Although the numbers are small and the difference not significant, this observation of an increase in the risk of haemorrhagic stroke has been reported in studies of statins in the literature. But because the effect of the combination on ischaemic stroke was beneficial, the overall effect of treatment on stroke taken as a whole was statistically significantly positive. Missing information Risk Exposure during pregnancy and lactation Use in children (limited clinical trial What is known Patients are advised not to take ezetimibe/simvastatine if they are pregnant, are trying to get pregnant or think you may be pregnant. If patients get pregnant while taking ezetimibe/simvastatine, they should stop taking it immediately and tell their doctor. Patients are advised not to take ezetimibe/simvastatine if they are breastfeeding, because it is not known if the medicine is passed into breast milk. Patients are advised to ask their doctor or pharmacist for advice before taking any medicine. Initiation of treatment must be performed under review of a specialist. Use in adolescents (10 to 17 years of age): The dose is 1 tablet Part V I: Summary of the risk management plan by product Page 32

5 Risk experience in children 10-17years of age, no clinical trial experience in children younger than 10 years of age) What is known ezetimibe/simvastatine by mouth once a day (a maximum dose of 10 mg/40 mg once daily must not be exceeded). There is limited data on use in children younger than 10 years of age. Use in this patient group is not recommended. 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 Patient Information Leaflet (PIL). 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 Not applicable. VI.2.7 Summary of changes to the risk management plan over time Not applicable. Part V II: A nnexes Page 33