Elements for a Public Summary. PhV Page 54/143

Transcription

1 VI.2 Elements for a Public Summary PhV Page 54/143

2 VI.2.1 Overview of disease epidemiology Hypercholesterolaemia Hypercholesterolemia (high levels of cholesterol in the blood) is usually discovered during routine screening and does not produce symptoms. In most patients, the Western lifestyle of a high-fat diet plus inherited genes appears to cause hypercholesterolemia. Hypercholesterolemia is more common in individuals with a family history of the condition. Hypercholesterolemia gives an increased risk of heart diseases. In adults, hypercholesterolemia increases with age and hypercholesterolemia is more common in men younger than 55 years and in women older than 55 years. Some patients with elevations of both bad cholesterol and fatty substances called triglycerides may have hypercholesterolemia along with some other condition such as insulin resistance or obesity that causes high triglyceride values(1). Homozygous familial hypercholesterolaemia Familial hypercholesterolemia (FH) is a disorder genetically passed on from parent to child that causes severe elevations in total cholesterol and bad cholesterol or the specific fatprotein called low-density lipoprotein cholesterol (LDLc). Most patients with inherited mutated gene from both mother and father (homozygous FH) do not survive adulthood beyond age 30 years unless treated by liver transplantation, LDL removal from blood, or shortening of the small intestine, to dramatically lower their LDLc levels. These patients may have symptoms consistent with decreased blood flow to the heart, blocked arteries, blocked arteries in the brain, or narrowing of aorta. Such symptoms may be confused with conditions that are less serious, unless the diagnosis of homozygous FH is considered. The occurrence of homozygous FH is 1 case per 1 million persons(2). Prevention of Cardiovascular Events Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels. CVDs are the number one cause of death globally. An estimated 17.3 million people died from CVDs in 2008, representing 30% of all global deaths. Of these deaths, an estimated 7.3 million were due to heart disease and 6.2 million were due to stroke. Low- and middleincome countries are more affected: over 80% of CVD deaths take place in low- and middleincome countries and occur almost equally in men and women. Most heart diseases can be prevented by addressing the related causes such as tobacco use, unhealthy diet and obesity, physical inactivity, high blood pressure, diabetes and raised fatty substances in the blood. 9.4 million deaths each year, or 16.5% of all deaths can be attributed to high blood pressure. This includes 51% of deaths due to strokes and 45% of deaths due to coronary heart disease(3). VI.2.2 Summary of treatment benefits Hypercholesterolaemia Several studies have been done comparing the fat lowering effect and safety of rosuvastatin and other statins. In most of the studies the main outcome was decrease in the specific fatprotein called low-density lipoprotein cholesterol (LDL-C). Two large studies of 2933 patients over 18 years, compared rosuvastatin with other statins (atorvastatin, pravastatin or simvastatin) 5-80 mg over 6-12 weeks. Main outcome was decrease in LDL-C. produced meaningfully decrease compared to other the statins. A study of 263 patients with type 2 diabetes compared the effect of rosuvastatin with atorvastatin over 24 week period. Main outcome was the change in a specific fat-protein proportion (apolipoprotein B (apob) and apob/apolipoprotein A1 (apoa1) ratio), which has been suggested as a better forecaster for heart related events. A greater decrease in fat-protein proportion was seen with rosuvastatin than atorvastatin and an important greater decrease in the bad fat-protein (LDL-C) was also found with rosuvastatin. PhV Page 55/143

3 Homozygous familial hypercholesterolaemia (hofh) A 18 weeks study compared the effect of rosuvastatin 80 mg and atorvastatin 80 mg in 44 patients aged 8-63 years. The decrease from the start in LDL cholesterol was 22 % overall and rosuvatstatin was found to have beneficial value in the management of hofh. Prevention of cardiovascular events An international study assessed change in percent of fatty deposit which develops within the walls of arteries (atheroma volume (PAV)) from start to 24 months of treatment in 507 patients. All patients received thorough statin treatment with rosuvastatin (40 mg/day). A important decrease in the fatty deposit within the walls of arteries was found. VI.2.3 Unknowns relating to treatment benefits Based on the currently available data an important gap in knowledge was identified in relation to the efficacy of rosuvastatin. There is limited clinical trial experience in children aged 6-17 and no clinical trial experience in children less than 6 years of age. VI.2.4 Summary of safety concerns Important identified risks Risk What is known Preventability Effect on muscles conneted to the bone (Skeletal muscle effects) Effects on muscles conneted to the bone e.g. muscle pain, muscular disease and, rarely, rapid destruction of muscle tissue, have been reported in rosuvastatin-treated patients with all doses and in particular high doses. is not recommended for use in patients with muscle pain. Patients with the following symptoms or diseases should not be treated with high doses of rosuvastatin: - moderate kidney impairment - underactive thyroid gland - personal or family history of hereditary muscular disorders - previous history of poisoning of muscles with another cholesterol lowering product - alcohol abuse - situations where an increase in plasma levels (a composite of the blood) may occur - Asian patients - Use of other cholesterol lowering products at the same time with rosuvastatin Yes, the risk can be minimised by taking a lower dose and avoiding coadministration of certain medicines. All patients starting therapy with rosuvastatin, or whose dose of rosuvastatin is being increased, should be advised of the risk of skeletal muscle effects and told to report promptly any unexplained muscle pain, tenderness or weakness. Effects on the liver (Hepatic effects) As with other cholesterol lowering products, a increase of liver enzymes related to larger doses has Yes, it is recommended that liver function tests should be carried out prior to, and 3 PhV Page 56/143

4 Risk What is known Preventability been seen I a small number of patients taking rosuvastatin. However in most cases the symptoms were mild and temporary. months following, the start of treatment. is not recommended for use in patients with active liver disease including unexplained, continuing elevations of liver enzymes. Effects on the kidneys (renal effects) should be used with caution in patients who consume large amounts of alcohol and/or have a history of liver disease. is not recommended for use in patients with severe kidney impairment. Protein in the urine, has been observed in patients treated with higher doses of rosuvastatin, where it was temporary or irregular in most cases. Protein in the urine has not been shown to be predictive of acute or progressive kidney disease. Review of data from clinical trials and post-marketing experience to date has not identified a causal association between proteinuria and acute or accelerating kidney disease. Blood in the urine has been observed in patients treated with rosuvastatin and data has shown that the occurrence is low. Yes, it is recommended that assessment of kidney function should be considered during routine follow-up of patients treated with a dose of 40 mg. In light of the increased reporting rate of adverse reactions with the 40 mg dose compared to lower doses, the recommended start dose is 5 mg in patients with moderate kidney impairment. Important potential risks Risk Effect on childrens weight, height, Body Mass Index and their maturation (Impactt on growth, weight, BMI and sexual maturation in children >6 to 17 years) What is known (Including reason why it is considered a potential risk) The evaluation of height, weight, and body mass index (BMI) and maturation of children 6 to 17 years of age taking rosuvastatin is limited to a two-year period. After two years of study treatment, no effect on growth, weight, BMI or maturation was found. Experience in children with an inherited condition which causes high levels of LDL (homozygous familial hypercholesterolaemia) is limited to a small number of children aged between 8 and 17 years. PhV Page 57/143

5 Missing information Risk Use in children younger than 6 years What is known The safety and efficacy of use in children younger than 6 years has not been studied. Therefore, rosuvastatin is not recommended for use in children younger than 6 years 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. This medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). How they are implemented in each country however will depend upon agreement between the manufacturer and the national authorities. These additional risk minimisation measures are for the following risks: Effect on muscles conneted to the bone, liver effects and kidney effects (Skeletal muscle effects, Hepatic effects and renal effects) Dear Healthcare Professional Communication (DHPC) (Completed as of RMP version 2.0) Objective and rationale: To communicate to health-care professionals (doctors, pharmacists, nurses etc.) the risk of skeletal muscle effects, hepatic effects and renal effects and the procedures related to the appropriate management of this risk to minimise its occurrence and its severity. Proposed action: Summary description of the DHPC DHPC to be provided to prescribing physicians includes advice on: Contraindications Dosing Recommendations Special warning and precautions for the risk of skeletal muscle effects, hepatic effects and renal effects VI.2.6 Planned post authorisation development plan No post-authorisation safety or efficacy studies are ongoing or are planned to be conducted for rosuvastatin. VI.2.7 Summary of changes to the Risk Management Plan over time Major changes to the Risk Management Plan over time Version Date Safety Concerns Comment Important identified risks Skeletal muscle effects Hepatic effects Renal effects Initial version Important identified risks Skeletal muscle effects This RMP was updated with information regarding use in paediat- PhV Page 58/143

6 Version Date Safety Concerns Comment Hepatic effects ric population after an Renal effects Article 29 Referral for Important potential risks Crestor and associated Impact on growth, weight, names (EMEA/H/A-29- PAE/1378) was finalised. The RMP has BMI and sexual maturation in children >6 to 17 years been updated to reflect Missing information this outcome. Furthermore, the product Tin- Use in children younger than 6 years taros (CZ/H/0388/ ) was added to the RMP. PhV Page 59/143