EMA/577184/2015 Summary of the risk management plan (RMP) for Repatha (evolocumab) This is a summary of the risk management plan (RMP) for Repatha, which details the measures to be taken in order to ensure that Repatha is used as safely as possible. For more information on RMP summaries, see here. This RMP summary should be read in conjunction with the EPAR summary and the product information for Repatha, which can be found on Repatha’s EPAR page. Overview of disease epidemiology Repatha is a medicine used to treat adults with primary hypercholesterolaemia (high blood cholesterol levels, in particular of the type ‘LDL-cholesterol’ or ‘bad’ cholesterol). Primary means that the disease is generally the result of a genetic abnormality. Primary hypercholesterolaemia includes heterozygous familial (when the genetic abnormality is inherited from only one parent) and non-familial disease (when the genetic abnormality arises spontaneously without a family history). Between 2 and 5 out of 1000 European citizens are believed to be affected. Repatha is also used to treat mixed dyslipidaemia (abnormal levels of fats in blood, including high levels of LDL-cholesterol). Repatha is also used to treat adults and children aged 12 years and over who have ‘homozygous familial hypercholesterolemia’ (a severe form of hypercholesterolaemia caused by a genetic abnormality inherited from both parents). This condition affects about 1 in 1 million people. Summary of treatment benefits The active substance in Repatha, evolocumab, is a monoclonal antibody, a type of protein. In primary hypercholesterolaemia and mixed dyslipidaemia, Repatha was studied in 9 main studies involving around 7,400 adult patients, including patients with heterozygous familial disease. Some of the studies looked at Repatha taken on its own, while others studied Repatha in combination with other fat-lowering medicines, including patients on the maximum recommended doses of statins. Some studies compared Repatha with placebo (a dummy treatment) and others to another medicine (ezetimibe). These studies found a substantial reduction in blood levels of LDL-cholesterol (around 60 to 70% more than placebo, and of around 40% more than ezetimibe) from week 10 to week 12 of the study and at the end of 12 weeks. In homozygous familial hypercholesterolaemia, Repatha was studied in 2 main studies involving 155 patients, which included 14 children older than 12 years. One of these studies showed that Repatha given together with other fat-lowering medicines reduced fat levels in the blood after 12 weeks of treatment (around 15 to 32% more than placebo given on top of other fat lowering medicines). A second study showed that long-term use of Repatha achieved a sustained reduction of fat levels in the blood in these patients during 28 weeks of treatment. Page 1/8 Unknowns relating to treatment benefits Repatha has not been studied in patients with severe kidney or liver disease; however, Repatha is not expected to be harmful to the kidneys or liver. Although Repatha lowers levels of fats in the blood, which are risk factors for cardiovascular disease, it is not known if Repatha will reduce cardiovascular disease. Studies to measure the longer term effects of Repatha on the cardiovascular system (e.g. reduction in the risk of heart attack or stroke as a result of the lower cholesterol levels) are currently underway. Summary of safety concerns Important identified risks There are no important identified risks. Important potential risks Risk What is known Allergic reactions Repatha may cause allergic reactions. Symptoms of an allergic reaction may (hypersensitivity) include headache, rash, itching, flushing, swelling, shortness of breath, nausea, and sometimes vomiting. Severe allergic reactions can cause dizziness, severe skin reactions, difficulty breathing or swallowing, and a decrease in blood pressure, and could be life threatening. Generally, patients recover when their allergic reaction is treated. Immunogenicity (the As with any medicine that is a protein (e.g. monoclonal antibody) there is a ability of the medicine potential for the body to react to the protein and make antibodies against to trigger an immune Repatha, which could cause Repatha not to work. While a small number of response) subjects have shown an immune response to Repatha, this did not affect the ability of Repatha to work. Missing information Risk What is known Use in pregnant and Repatha has not been studied in women who are pregnant. breastfeeding women In animal studies there were no effects on pregnancy or the growth and development of young animals. As expected, cholesterol levels were lowered in animals which were given Repatha during pregnancy. Repatha should not be used during pregnancy unless the clinical condition of the woman requires treatment with Repatha. Repatha has not been studied in women who are breastfeeding, so it is not known whether it causes any side effects in breastfeeding infants. It is also not known if Repatha will pass onto breast milk if the mother is receiving Repatha. A decision must be made whether to discontinue breastfeeding or discontinue/abstain from Repatha therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Use in infants, Repatha has only been studied in a very small number of children with genetic Page 2/8 Risk What is known children, and abnormalities affecting their cholesterol levels (heterozygous familial adolescents hypercholesterolaemia and homozygous hypercholesterolaemia) so it is not (paediatric patients) fully known at present whether it is safe and effective to treat children with Repatha. Fourteen patients aged between 12 and 18 years have been treated with Repatha in clinical studies so far. Repatha use in paediatric patients continues to be studied. Use in older Repatha has been studied in older patients. In clinical studies, 26.2% of patients (75 years or patients were 65 years or older, and 3.7% of patients were 75 years or older. older) There did not appear to be any differences in the type or number of side effects compared with younger patients, but this will continue to be monitored. Use in people with Repatha has not been studied in patients with severe kidney problems. As severe kidney Repatha is not broken down by the kidneys, so kidney disease is not expected problems (severe to change the action of Repatha. Repatha should be used with caution in renal impairment) patients with severe kidney problems. Use in people with Repatha is not broken down in the liver. A study in subjects with mild to severe liver problems moderate liver disease did not show any increase in side effects for these subjects, however it has not been studied in patients with severe liver problems. Repatha should be used with caution in patients with severe liver problems. Use in patients with Due to inconsistent findings in the literature and limited number of subjects hepatitis C with hepatitis C exposed to Repatha, no meaningful conclusions can be drawn. This will continue to be monitored. Use in patients with Repatha has not been studied in patients with type 1 diabetes. However, type 1 diabetes Repatha’s use in subjects with type 1 diabetes is currently being studied. Use in patients with Repatha has not been studied in patients infected with the human human immunodeficiency virus (HIV). However, Repatha’s use in patients with human immunodeficiency immunodeficiency will be studied. virus Long-term use People with rare inherited conditions that cause very low cholesterol levels do including effects of appear to be healthy. In the clinical studies, there were 614 subjects with very very low levels of low levels of LDL-C exposed to Repatha for over 24 months. No increase in LDL-C side effects with very low LDL-C levels have been seen. This will continue to (below 40 mg/dL or be studied. below 1.03 mmol/L) Summary of risk minimisation measures by safety concern All medicines have a summary of product characteristics (SmPC) which provides physicians, pharmacists and other healthcare professionals with details on how to use the medicine, and also describes the risks and recommendations for minimising them. Information for patients is available in lay language in the package leaflet. The measures listed in these documents are known as ‘routine risk minimisation measures’. Page 3/8 The SmPC and the package leaflet are part of the medicine’s product information. The product information for Repatha can be found on Repatha’s EPAR page. This medicine has no additional risk minimisation measures. Planned post-authorisation development plan List of studies in post-authorisation development plan Study/activity Objectives Safety concerns Status Planned date for (including study /efficacy issue submission of number) addressed (interim and) final results 20110110 To characterise the Long-term use Ongoing Q1 2017 Multicenter, safety and tolerability of including effects of Controlled, Open long-term LDL-C below 40 label Extension administration of mg/dL or below 1.03 (OLE) Study to Repatha. mmol/L Assess the Long term Safety and To characterise the Efficacy of efficacy of long term Evolocumab (AMG administration of 145) Repatha as assessed by LDL-C, non HDL-C, ApoB, total cholesterol/HDL-C ratio, and ApoB/ApoA1 ratio in subjects with hypercholesterolaemia. 20110118 To evaluate the effect of Long-term use Ongoing No later than Q2 A Double blind, treatment with including effects of 2018 Randomized, Repatha, compared with LDL-C below