Drug Regulatory Affairs Praluent Summary of the Risk Management Plan (RMP) for Praluent (alirocumab) Document version: 02 Document date: MAY 2018
Summary of the risk management plan (RMP) for Praluent (alirocumab) The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier for market approval of a medicine. The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimize them. The RMP summary of Praluent is a concise document and does not claim to be exhaustive. As the RMP is an international document, the summary might differ from the Arzneimittelinformation / Information sur le medicament approved and published in Switzerland, e.g. by mentioning risks occurring in s or indications not included in the Swiss authorization. Please note that the reference document which is valid and relevant for the effective and safe use of Praluent in Switzerland is the Arzneimittelinformation/ Information sur le medicament (see www.swissmedicinfo.ch) approved and authorized by Swissmedic. Sanofi-aventis (suisse) sa is fully responsible for the accuracy and correctness of the content of this published summary RMP of Praluent. Overview of disease epidemiology PRALUENT, which contains the active substance alirocumab, is a medicine used to treat adults with primary hypercholesterolemia (high blood cholesterol levels, in particular LDL-C or bad cholesterol). It is used in combination with other lipid-lowering therapies, or alone in patients not tolerating such therapy. Primary means that the disease is generally the result of a genetic abnormality. Primary hypercholesterolemia includes heterozygous familial (when the genetic abnormality is inherited from only one parent or hefh) and non-familial disease (when the genetic abnormality arises by chance without a family history, non-fh). Between 2 and 5 out of 1000 European citizens are believed to be affected. PRALUENT is also used to treat mixed dyslipidemia (abnormal levels of fats in blood, including high levels of LDL-C). Summary of treatment benefits PRALUENT has been studied in 10 main studies involving over 5000 adult patients with hypercholesterolemia (including patients with heterozygous familial disease) and mixed dyslipidemia. Some studies looked at PRALUENT taken on its own, while others studied PRALUENT in combination with other fat-lowering medicines, including patients on the maximum recommended doses of statins. Some studies compared PRALUENT with placebo (a dummy treatment) and others to another medicine for hypercholesterolemia (ezetimibe). These studies showed that when PRALUENT was given on top of a statin it led to a substantial reduction in blood levels of LDL-C (between 39% and 62% more than placebo) after 6 months of treatment. When given on top of standard treatment or on top of placebo, PRALUENT produced a 24% to 36% greater reduction in blood levels of LDL-C than ezetimibe.
Unknowns relating to treatment benefits PRALUENT has not yet been evaluated in children or adolescent s. In addition, treatment benefits are unknown in patients with homozygous familial hypercholesterolemia (HoFH, a severe form of the disease), since they were not part of the involved in the clinical studies. Summary of safety concerns Table 1 - Important identified risks Risk What is known Preventability Ability of the medicine to trigger an immune response (Immunogenicity) General allergic/hypersensitivity reactions after being given the medicine (Systemic hypersensitivity reactions) As with any medicine that is a protein (eg, monoclonal antibody) there is a potential for the body to make anti-drug antibodies against PRALUENT, which could cause PRALUENT not to work. In clinical studies, development of antibodies against PRALUENT was observed in a small number of patients usually, without other signs or symptoms. PRALUENT may rarely cause hives (urticaria) or hypersensitivity vasculitis (a hypersensitivity reaction whose symptoms include diarrhoea, rash, or purple-colored spots on the skin known as purpura). Reddish skin spots sometimes with blisters (nummular eczema) are also rarely reported. Unknown Patients should avoid taking PRALUENT in case of known allergic reaction to alirocumab or to any of its other ingredients Table 2 - Important potential risks Risk Blurred vision linked to cataracts (loss of transparency of the lens of the eye) in patients with very low cholesterol in the blood (Cataract [in the context of very low LDL- C]) Fehler! Verweisquelle konnte nicht gefunden werden. Problems with mental function (Neurocognitive disorders) a ie, less than 25 mg/dl (0.65 mmol/l) LDL-C: Low Density Lipoprotein-Cholesterol What is known Cases of cataract have been diagnosed more frequently in patients treated with alirocumab than in those treated with placebo, when they had very low cholesterol blood levels. Cases of abnormal cognitive (mental) function such as memory impairment, have been reported with similar incidence in patients given alirocumab and placebo in the clinical studies.
Risk Use in children and adolescents Use in pregnant and breastfeeding women Use in patients with severe problems with the liver (use in severe hepatic impairment) Use in patients infected with hepatitis C (Use in chronic HCV carrier/hepatitis) Long-term use above 5 years) Clinical impact of very low LDL-cholesterol a for extended period of time Influence of PRALUENT on sex hormones in men and women (Influence of alirocumab on gonadal steroid hormones and gonadotropins (in men and women)) Table 3 - Missing information a ie, less than 25 mg/dl (0.65 mmol/l) HCV: Hepatitis C Virus; LDL-C: Low Density Lipoprotein-Cholesterol What is known PRALUENT has not been evaluated in children or adolescents. PRALUENT is not recommended during pregnancy or breastfeeding. PRALUENT has not been evaluated in pregnant or breastfeeding women. Although PRALUENT passes from the blood supply of the mother to the unborn baby in animal studies, it had no harmful effects on the offsprings. As it is unknown whether PRALUENT passes to human milk, the doctor should consider advising the woman discontinue breastfeeding or to stop taking the medicine. PRALUENT has not been evaluated in patients with severe liver disease. PRALUENT was evaluated in subjects with mild and moderate reduction in liver function and there was no effect on the medicine s concentration in blood. PRALUENT has not been evaluated in patients infected with hepatitis C. Chronic use for up 18 months has been extensively evaluated. The evaluation of the use of PRALUENT for up to 5 years is ongoing. PRALUENT has not been evaluated for longer than 5 years. As mentioned above, cataracts have been diagnosed more frequently in patients treated with alirocumab than placebo, when they had very low cholesterol blood levels. Other clinical impact of very low LDL-C is unknown at this stage. Some cholesterol is used by the body to make other substances, including sex hormones. Limited information is available on the influence of PRALUENT on sexual hormones in men and women. Summary of additional risk minimization measures by safety concern All medicines have a 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 minimizing them. Information for patients is available in lay language is provided in the PL. The measures included in these documents are known as routine risk minimization measures. The SmPC and the package leaflet are part of the medicine s product information. The product information for PRALUENT can be found on PRALUENT s European Public Assessment Report (EPAR) page. This medicine has no additional risk minimization measures.
Planned post authorization development plan Table 4 - List of studies in post-authorization development plan /activity (including study number) Objectives Safety concerns/efficacy issue addressed Status Planned date for submission of (interim and) final results LTS11717 Long-term safety of alirocumab 150 mg every two weeks in patients with non-fh or hefh at high cardiovascular risk not adequately controlled with a statin with or without other lipid modifying therapies (LMTs) Long-term safety of EFC12492 (FH I) two weeks in patients with hefh not adequately controlled with statin with or without other LMTs CL-1112 (FH II) two weeks in patients with hefh not adequately controlled with statin with or without other LMTs EFC12732 (HIGH FH) alirocumab 150 mg every two weeks in patients with hefh not adequately controlled with statin with or without other LMTs and with LDL-C 160 mg/dl (4.14 mmol/l) or more CL-1308 (CHOICE I) alirocumab 300 mg every four weeks or 75/150 mg every two weeks versus placebo in patients with hypercholesterolemia at moderate to very high cardiovascular risk, not adequately controlled with LMT
/activity (including study number) Objectives Safety concerns/efficacy issue addressed Status Planned date for submission of (interim and) final results EFC11569 (COMBO II) two weeks in patients at high cardiovascular risk with hypercholesterolemia not adequately controlled with statin therapy EFC13672 alirocumab versus placebo in Japanese patients with hefh or high cardiovascular risk patients with hypercholesterolemia not adequately controlled with LMT alirocumab in Japanese PDY13670 Pharmacodynamic effect of repeated doses of alirocumab every two weeks on lipids and lipoprotein metabolism Q4 2016 EFC13786 (CHOICE II) alirocumab 150 mg every four weeks or 75/150 mg every two weeks versus placebo in patients with hypercholesterolemia not treated with statin LTS13463 (OLE of hefh studies) Open-label extension study of FH I, FH II, HIGH FH, and LTS11717 to assess longterm safety and efficacy of two weeks in patients with hefh Ongoing Q2 2018 OLE of CL-1119 (ALTERNATIVE) two weeks in statin intolerant patients with primary hypercholesterolemia (hefh and non-fh) at moderate or high CV risk Ongoing Q2 2018 CL-1018 (OLE study of the GOF study) Open-label extension study to CL-1018 study to assess the long-term efficacy and safety of alirocumab 150 mg every two weeks in patients with autosomal dominant hypercholesterolemia (up to 36-month duration) Ongoing Q2 2018
/activity (including study number) Objectives Safety concerns/efficacy issue addressed Status Planned date for submission of (interim and) final results CL-1032 (OLE of R727-CL-1003) Open-label extension study to CL-1003 to assess long-term safety and tolerability of alirocumab 150 mg every two weeks in patients with hefh receiving concomitant statins with or without other LMTs (up to 48-month duration) Ongoing Q3 2017 OLE of EFC13786 (CHOICE II) Open-label extension study of CHOICE II to assess longterm efficacy and safety of alirocumab 150 mg every four weeks or 75/150 mg every two weeks versus placebo in patients with hypercholesterolemia not treated with a statin Ongoing Q2 2018 EFC11570 (CV OUTCOMES) Effect of alirocumab (75 mg/ml or 150 mg/ml, every two weeks) versus placebo on the occurrence of cardiovascular events in patients who had recently experienced an acute coronary syndrome (up to 64-month duration) Long-term efficacy and safety of alirocumab in considered Ongoing Q3 2018 LTS14580 (post-odyssey OUTCOMES registry study (PASS) prospective observational study) Evaluate safety in long-term use (more than 5 years) Evaluate potential clinical impact of very low LDL-C for extended period of time Specific neurocognitive (mental function) evaluation Influence of alirocumab on gonadal steroid hormones and gonadotropins (in men and women) Safety in long-term use (more than 5 years) Clinical impact of very low LDL-C for extended period of time Neurocognitive disorders Measurement of gonadal steroid hormones and gonadotropins (in men and women) Ongoing Q3 2022 (Final report) A PASS in patients infected with HIV Gather relevant safety data in patients infected with HIV Safety data in patients infected with HIV Planned Q2 2016 (Protocol submission) A trial in which there will be a dedicated prospective assessment of neurocognitive function Prospective assessment of neurocognitive function (mental function) using a neurocognitive battery of tests Evaluate neurocognitive disorders considered as potential risk Planned Q2 2016 (Protocol submission)
/activity (including study number) Drug utilization survey Objectives To assess the effectiveness of dosing recommendation as per the product information Safety concerns/efficacy issue addressed LDL-C levels in respect to dosing recommendation Status Planned date for submission of (interim and) final results Planned Q2 2016 (Protocol submission) ACS: Acute Coronary Syndrome; ADH: Autosomal Dominant Hypercholesterolemia; CV: Cardiovascular; hefh: Heterozygous Familial Hypercholesterolemia; LDL-C: Low Density Lipoprotein-Cholesterol; LMT: Lipid Modifying Therapy; Non-FH: Non- Familial Hypercholesterolemia; OLE: Open-Label Extension; Q2W: Once in 2 weeks; Q4W: Once in 4 weeks; HIV: Human Immunodeficiency Virus, PASS: Post-Authorization Safety. Studies which are a condition of the marketing authorization None of the studies in the previous section are a condition of the marketing authorization for PRALUENT. Summary of changes to the RMP over time Version Date Safety concerns Table 5 - Summary of changes to the RMP over time Comment 2.0 10-Mar-2016 - Revised commitments timelines regarding several category 3 studies (CL-1308, EFC13786, LTS11717, EFC12492, CL-1112, EFC12732, EFC11569, EFC13672 and PDY13760 studies), and their status, in Part III, Part IV, and Part VI. 3.0 12-Jan-2017 - The due dates for the provision of the final study report for 6 category 3 studies (MEA011=OLE of CL-1119, MEA012=OLE of CL-1018, MEA013=CL-1032, MEA0 10=LTS13463, MEA014=OLE of EFC13786, MEA015=EFC11570) have been updated in Part III, Part IV, and Part VI. RMP: Risk Management Plan; OLE: Open Label Extension.