Elements for a Public Summary. Overview of disease epidemiology. Cardiovascular Events

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1 VI.2 VI.2.1 Elements for a Public Summary Overview of disease epidemiology Cardiovascular Events Each year cardiovascular disease (CVD) causes 3.9 million deaths in Europe and over 1.8 million deaths in the European Union (EU). CVD accounts for 45% of all deaths in Europe and 37% of all deaths in the EU. Hypercholesterolaemia Hypercholesterolemia means high level of cholesterol in blood. Around 133 million suffer from so-called bad cholesterol in the EU s five biggest countries Germany, France, Italy, Spain and the UK -, according to the World Health Organisation (WHO). Overall, Europe is the continent with the highest prevalence of the chronic disease, latest statistics show. Europe has the highest prevalence of high cholesterol in the world, with 54% for both men and women. High cholesterol or bad cholesterol contributes to 2.6 million deaths per year, worldwide. The main causes for high cholesterol are both an unhealthy lifestyle and/or genes. Homozygous Familial Hypercholesterolaemia (HoFH) Familial hypercholesterolemia (FH) is a disorder genetically passed on from parents to a children that causes severe elevations in total cholesterol and bad cholesterol known as LDL-C (low-density lipoprotein cholesterol). The worldwide prevalence of HoFH is generally estimated to be one in a million. VI.2.2 Summary of treatment benefits Ezetimibe/simvastatin is indicated for prevention of heart and blood vessel related disorders, high levels of cholesterol in blood (hypercholesterolaemia) and hereditary condition involving hypercholesterolaemia in families (HoFH). Ezetimibe/Simvastatin are two lipid-lowering medicines with complementary mechanisms of action. The lipid levels are reduced by selectively inhibiting the intestinal absorption of cholesterol and related plant sterols. It also inhibits the synthesis of cholesterol originated or produced by the body. A 12-week clinical study conducted on 50 patients with HoFH showed that Ezetimibe administered with atorvastatin (40 or 80 mg) or simvastatin (40 or 80 mg) significantly reduced LDL-C compared with increasing the dose of simvastatin or atorvastatin (40 to 80 mg) monotherapy. VI.2.3 Unknowns relating to treatment benefits No clinical trial experience is available regarding use in pregnancy and lactation. The clinical experience in paediatric and adolescent patients (aged years old) is limited and use in children less than 10 years is not recommended due to insufficient data on safety and efficacy.

2 VI.2.4 Summary of safety concerns Table 1: Important Identified Risk(s) Risk(s) What is known Preventability Muscular weakness/ breakdown of muscles (Rhabdomyolysis /myopathy) Abnormal Liver Function Hypersensitivity Cases of myopathy and rhabdomyolysis have been reported with the use of both ezetimibe and simvastatin. Caution should be exercised in patients with predisposing factors for rhabdomyolysis: - Elderly (age 65 years) - Female gender - Kidney impairment - Uncontrolled under active thyroid gland - Personal or family history of hereditary muscular disorders - Previous history of muscular toxicity with a statin or fibrate - Alcohol abuse. In controlled coadministration trials in patients receiving ezetimibe with simvastatin, elevations of liver enzymes ( 3 X ULN) have been observed. There have been rare postmarketing reports of fatal and non-fatal liver failure in patients taking statins, including simvastatin. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe liver insufficiency, ezetimibe/ simvastatin is not recommended. Over sensitivity, including rash, itchy skin rash, severe allergic responses and swollen face, lips, throat or tongue has been reported with the use of ezetimibe/simvastatin or with use of one of the individual drugs. Yes, the risk can be minimised by taking a lower dose of simvastatin and avoiding the coadministration of certain medicines. All patients starting therapy with ezetimibe/simvastatin, or whose dose of ezetimibe/ simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Yes, it is recommended that liver function tests be performed before treatment with ezetimibe/simvastatin begins and thereafter when clinically indicated. If serious liver injury with clinical symptoms and/or hyperbilirubinaemia or jaundice (yellowing of the skin or whites of the eyes) occurs during treatment with ezetimibe/simvastatin promptly stop therapy. If an alternate cause is not found, do not restart ezetimibe/simvastatin. Yes, by not taking ezetimibe/simvastatin if the patient is allergic to ezetimibe, simvastatin, or to any of the other ingredients in the product. Drug interactions warfarin, another coumarin anticoagulant, or fluindione Drug interactions with ciclosporin There have been reported cases of increased blood clotting time (increased INR) in patients taking ezetimibe together with warfarin or fluindione. In two clinical trials with simvastatin, the effect of coumarin antiocoagulants in patients taking both drugs was modestly potentiated. The risk of muscular weakness and/or breakdown of muscles (myopathy/rhabdomyolysis) is increased by Yes, by taking blood samples (measuring the International Normalised Ratio (INR)). Yes, by avoiding the intake ciclosporin together with ezetimibe/simvastatin.

3 Risk(s) What is known Preventability taking simvastatin/ezetimibe together with ciclosporin. Table 2: Important Potential Risk(s) Risk(s) Inflammation of the pancreas (pancreatitis) Inflammation of the gall bladder or gallstones (cholecystitis/cholelithiasis) Lung disease affecting the tissue and space around the air sacs of the lungs (Interstitial lung disease) What is known The adverse reaction has been reported with use of ezetimibe/simvastatin or during use with one of the individual drugs. The adverse reactions have been reported with use of ezetimibe/simvastatin or during use with one of the individual drugs. Cases of interstitial lung disease have been reported with some statins, including simvastatin, especially with long term therapy. Presenting features can include difficulty breathing, nonproductive cough and deterioration in general health (fatigue, weight loss and fever). Simvastatin hypersensitivity syndrome New onset diabetes/impaired glucose metabolism Bleeding inside the brain (Haemorrhagic Stroke) If it is suspected that a patient has developed interstitial lung disease, ezetimibe/ simvastatin therapy should be discontinued. An apparent hypersensitivity syndrome has been reported rarely which can include some of the following features: angiooedema (serious allergic reaction which causes swelling of the face or throat), lupus-like syndrome (a condition that mimics the symptoms of systemic lupus erythematosus such as inflammation and tissue damage), polymyalgia rheumatic (muscle gout), dermatomyositis (connective tissue disease that is characterized by inflammation of the muscles and the skin), vasculitis (inflammation of blood vessels), thrombocytopaenia (reduction in platelets in the blood), eosinophilia (increase in white blood cells), red blood cell sedimentation rate increased (a sedimentation rate is a blood test that detects nonspecific inflammation in the body, increased values may suggest inflammation), arthritis and arthralgia (joint pain/inflammation), urticaria (itchy skin rash), photosensitivity reaction (reactions due to sensitivity to light), pyrexia (fever), flushing, dyspnoea (difficulty in breathing) and malaise (a feeling of general discomfort and illness). Some evidence suggests that statins as a class raise blood sugar and in some patients, at high risk of future diabetes, may produce a level of increased blood sugar where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. The New onset diabetes/impaired glucose metabolism (fasting glucose 5.6 to 6.9 mmol/l, BMI > 30 kg/m², raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines. In a large study including over patients after acute coronary syndromes in treatment with simvastatin-ezetimibe or simvastatin monotherapy, there was an overall benefit for all strokes; however, the rate of haemorrhagic stroke was higher, although non-significant with simvastatin-ezetimibe than with simvastatin monotherapy.

4 Table 3: Missing Information Risk(s) Exposure during pregnancy and lactation Use in children (Limited clinical trial experience in children years of age. No clinical trial experience in children less than 10 years of age) What is known No clinical data are available on the use of ezetimibe/simvastatin during pregnancy. It is not known if the active components of ezetimibe/simvastatin are secreted into human breast milk. 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 ezetimibe/simvastatine by mouth once a day (a maximum dose of 10 mg/40 mg once daily must not be exceeded). There is limited clinical trial experience in children years of age. There is no clinical trial experience in children less 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 package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. The SmPC and the PL for Ezetimib-Simvastatin can be found in the Ezetimib-Simvastatin EPAR page. This medicinal product 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 Version Date Safety Concerns Comments May-2017 Important identified risk(s) 1. Hypersensitivity First version of the RMP.

5 Dec Drug interactions warfarin, another coumarin anticoagulant, or fluindione 3. Drug interactions with ciclosporin 4. Drug interactions with potent CYP3A4 inhibitors 5. Drug inter-actions with fusidic acid 6. Drug interactions with grapefruit juice 7. Drug interactions with diltiazem 8. Drug interactions with verapamil 9. Drug interactions with amlodipine 10. Drug interactions with fibrates 11. Drug interactions with niacin 1 g/day 12. Drug interactions with danazol 13. Drug interactions with amiodarone 14. Myopathy/rhabdomyolysis 15. Interstitial lung disease 16. Diabetes mellitus 17. Liver dysfunction Important potential risk(s) 1. Pancreatitis 2. Cholecystitis/cholelithiasis 3. Simvastatin hypersensitivity syndrome Missing information 1. Use during pregnancy 2. Use during lactation 3. Use in children Important identified risk(s) 1. Rhabdomyolysis/Myopathy 2. Abnormal Liver Function Information regarding the updated safety concerns aligned to respective sections of the RMP in

6 3. Hypersensitivity 4. Drug interactions warfarin, another coumarin anticoagulant, or fluindione 5. Drug interactions with ciclosporin accordance to the comments received from Netherlands regulatory authority. Important potential risk(s) 1. Pancreatitis 2. Cholecystitis/cholelithiasis 3. Interstitial lung disease 4. Simvastatin hypersensitivity syndrome 5. New onset diabetes/impaired glucose metabolism 6. Haemorrhagic Stroke Missing information 1. Exposure during pregnancy and lactation 2. Use in children (Limited clinical trial experience in children years of age. No clinical trial experience in children less than 10 years of age)