英文药名: Zocor(Simvastatin film-coated tablets) 中文药名: 舒降之（辛伐他汀片） 生产厂家: Merck & Co. Inc 药品介绍 药品名称和成分 舒降之（辛伐他汀片） 本品为血脂调节剂。适用于高脂血症、冠心病等。 通用名：辛伐他汀片 商品名：舒降之(ZOCOR) 英文名；Simvastatin Tablets 本品主要成份为：辛伐他汀 适应症 "高脂血症 对于原发必高胆固醇血症包括杂合子家族性高胆固醇血症高脂血症或混合性高酯血症的患者，当饮食控制及其它非药物治疗不理想时，结合饮食控制，本品可用于降低升高的总胆固醇、低密度脂滑白胆固醇、载脂蛋白B和甘油三酯，且可升高高密度脂蛋白胆固醇，从而降低密度脂蛋白胆固醇，高密度脂蛋白胆固醇及总胆固醇高密度脂蛋白胆固醇的比率。对于纯合予家族性高胆固醇血症患者，结合饮食控制及非饮食疗法，本品可用于降低升高的总胆固醇、低密度脂蛋白胆固醇和载蛋白B。 冠心病 对于冠心病合并高胆固醇血症的患者，本品适用于：降低死亡的危险性, 降低冠心病死亡及非致死性心肌梗塞的危险性, 降低中风和短暂性脑缺血的危险性, 降低心脏血管重建手术(冠状动脉搭桥术及经皮腔内冠状动脉成形术）的危险性，延缓冠状动脉粥样硬化的进程，包括减少新病灶及全堵塞的成形。" 用法用量 患者接受本品治疗以前，应接受标准的降胆固醇饮食并在治疗过程中继续维持。建议起始剂量为每天20mg，晚间一次服用，对于只需中度降低低密度脂蛋白胆固醇的患者，起始剂量为1Omg。 对于同时服用环孢菌素、贝特类或烟酸类药物以及严重肾功能不全的病人，其推荐剂量如下:推荐剂量范围为每天5-80mg，晚间一次服用，所用剂量应根据基础低密度脂蛋白胆固醇水平，推荐的治疗目标和患者反应进行个化调整，调整剂量应间隔4周或以上。 应定期监测胆固醇水平，当低密度脂蛋白胆固醇水平降至75mg/dL(1.94mmol/L)或血浆总脾固醇水平降至140mg/dL(3.6mmoI/L)以下时，应考虑减少本品的服用剂量。 *纯合子家族性高胆固醇血症 根据一项对照临床研究的结果，对纯合子家族性高胆固醇血症患者，本品的推荐剂量为每天40mg，晚间一次服用；或每天80mg，分20mg、20mg和晚间40mg三次服用。本品可与其它降脂疗法联使应用（如低密度胆蛋白提取法），当无法使用这些方法时，也可单独使用本品。 *服用环孢菌素 本品与环孢菌素同时服用时（见注意事项中的肌肉作用和药物相互作用）治疗的起始剂量为5mg／天，不应超过1Omg/天. *协同治疗 本品单独应用或与胆酸整合剂协同应用时均有效。若病人在服用本品时，同时应用环孢菌素，达那唑，吉非贝齐，其它贝特类或降脂剂量的烟酸(≥1克/天)，本品的剂量应超过每天1Omg。若病人与木品一起同时服用胺碘酮或维拉帕米，本品的剂量不应超过每天20mg，(见注意事项、肌病横纹肌溶解和药物相互作用)。 *肾功能不全的患者 由于木品经肾脏排泄不明显，故轻、中度肾功能不全患者不需调整剂量，然而对于严重肾功能不全的患者(肌酐清除率<30ml/分钟)应慎用木品。此类患者的起始剂量应为每天5mg，并密切监测。 如果您有任何疑问，请遵医嘱。 不良反应 本品一般耐受性良好，大部分不良反应轻微且为一过性。在对照临床研究中不足2％的病人因本品的不良反应而中途停药。在上市前的对照临床研究中，研究者认为与药物有关（分为可能、很可能或肯定）且发生率≥1％的不良反应有腹痛，便秘和胃肠胀气；发生率为0.5-0.9％的不良反应有疲乏无力和头痛。 禁忌 对本品任何成份过敏者 活动性肝脏疾病或无法解样的血清转氨酶持续升高者 怀孕和哺乳期妇女（见注意事项，怀孕和哺乳期妇女用药) 孕妇及哺乳期妇女用药 妊娠期妇女 妊娠期妇女禁用本品。尚未有妊娠期妇女服用辛伐他汀的安全性数据。在妊娠妇女中尚未进行辛伐他汀的对照临床试验。由于在孕期使用HMG-COA而导致的先天缺陷也很少有报道。但是，在对大约200名孕期的前三个月使用过辛伐他汀或其他密切相关的HMG-COA抑制剂的患者回顾性分析时发现，先天缺陷的发生率与普通人群相似。这种回顾的患者数在统计学上已经能够排除先天缺陷的发生率不高于普通发生的2.5倍或更高。 尽管没有明确的证据能说明怀孕妇女使用辛伐他汀会造成先天缺陷发生增多，但是辛伐他汀能降低胎儿的甲羟戊酸(胆固醇生物合成的前体)水平。动脉粥样硬化是慢性过程，所以妊娠期停用降酯药对治疗原发性高胆固醇血症的长期效果影响甚小。因此妊娠期妇女、准备怀孕或可能怀孕的妇女禁用本品。在怀孕期间应暂停使用本品(见禁忌)。 哺乳期妇女 目前还不了解辛伐他汀及其代谢产物是否经人乳分泌。因为许多药物经人乳分泌且可能引起的严重不良反应。服用本品的妇女不宜哺乳(见禁忌)。 儿童用药 儿童用药的安全性和有效性尚未确定。本品目前不推荐给儿童服用。 老年患者用药 在老年患者(>65岁)应用辛伐他汀的对照临床研究中，其降低总胆固醇和低密度脂蛋白胆固醇的效果与其它人群的结果相似，不良反应和实验窒检查异常的发生率也无明显增多。 注意事项 肌病、横纹肌溶解 与其它HMG-COA还原酶抑制剂一样，辛伐他汀偶尔能引起肌病，表现为肌肉痛，触痛乏力。并伴随肌酸激酶(CK)升高。超过正常上限的10倍。肌病有时形成横纹肌溶解，伴或不伴继发于肌红蛋白尿的急性肾衰，由此发生的致命性事件极少，血浆中HMG-COA还原酶抑制剂水平很高时肌病的危险增加，辛伐他汀与下列药物同时应用可能增加肌病／横纹肌溶解的危险： CYP3A4抑制剂：伊曲康唑、酮康唑、红霉素、克拉霉素、Telithromycin、HIV蛋白酶抑制或奈法唑酮，尤具在与高剂量的辛伐他汀合用时危险性增加(见药物相与作用，CYP3A4相互作用)。 其它药物： 吉非贝齐和其它贝恃类(非诺贝特除外)，或降脂剂量（>1克/天)的烟酸，尤其与高剂量的辛伐他汀合用时(见药物相与作用中的与单独应用能引起肌病的降脂药物的相互作用)，当非诺贝特与辛伐他汀合用时，没有证据显示肌病的危险超过它们单独使用时发生的危险总和。 环孢菌素或达那唑，尤其在与高剂量的辛伐他汀合用时(见药物相互作用，其它药物相与作用)。 胺碘酮或维拉帕米，与高剂量的辛伐他汀同用时危险增加(见药物相互作用，其它药物相互作用)，在一项正在进行的临床试验中，同时服用辛伐他汀80mg和胺碘酮的病人发生肌病的报道为6％。 地尔硫卓：同时服用地尔硫卓和辛伐他汀80mg会导致肌病的发生轻微增加。这种病人肌病发生的危险性约为1％，在临床试验中，服用辛伐他汀40mg的同时无论是否合用地尔硫卓，病人发生肌病的危险性相似，（见药物相互作用，其他药物相与作用）。 肌病/横纹肌溶解的危险是与剂量相关的。在临床试验中，病人在被仔细监测和排除一些相互作用的药物应用外，20mg的辛伐他汀肌病的发生率大约为0.03％，40mg为0.08%，80mg为0.4％。 因此 1.使用辛伐他汀时，要避免同时应用CYP3A4抑制剂(如伊曲康唑、酮康唑、红霉素、克拉霉素，Telithromycin、HIV蛋白酶抑制剂或奈法唑酮)，如果不可避免的与伊曲康唑、酮康唑，红霉索，克拉霉素或Telithromycin同用，在这些药物治疗期间要暂停辛伐他汀的应用，如果与说明书上所列的对CYP3A4有抑制作用的其它药物同用，要避免治疗剂量的应用，除非联合治疗的益处大于增加的危险。 2.同时服用环孢霉素。达那唑、吉非贝齐，其它贝特类（非诺贝特除外）或降脂剂量(>每天1克)的烟酸的病人，辛伐他汀的剂量不能超过每天10mg。应避免辛伐他汀与吉非贝齐联合应用，除非联合治疗的益处超过增加的危险，接受其它贝持类（非诺贝特除外），烟酸、环孢菌素或达那唑治疗的病人，在服用辛伐他汀时，应仔细权衡降脂的益处和联合应用的危险，因非诺贝特和辛伐他汀单独使用时都可能引起肌病，这两种药物的联合治疗应慎用。贝特类或烟酸与辛伐他汀相加通常不会进一步降低LDL-C，但可能会进一步降低TG和增加HDL-C。在小规模、短期的临床研究中，经仔细监测，贝特类或烟酸与低剂量的辛伐他汀联合应用没有肌病的发生。 3.同时服用胺碘酮或维拉帕米的病人，辛伐他汀的剂量不应超过每天20mg。联合应用时 除非带来的临床益处超过肌病增加的危险，应该避免辛伐他汀的剂量超过每天20mg。 4.所有病人在开始辛伐他汀治疗或增加辛伐他汀剂量时，要告知病人肌病的危险。若有不能解释的肌肉病，触痛或乏力要及时报告。如果诊断或可疑为肌病，要立即中止辛伐他汀治疗。存在这些症状和/或CK水平大于正常上限的lO倍提示为肌病。在多数病例中，当病人及时中止治疗后。肌肉症状和CK增加会恢复。开始用辛伐他汀治疗或增加剂量的病人，要定期测定CK水平，但这样的监测不能保证防止肌病的发生。 5.许多用辛伐他汀治疗发展为横纹肌溶解的病人病史复杂，包括肾功能不全，通常是长期糖尿病的后果，这样的病人应密切监视。用辛伐他汀治疗的病人在进行择期大手术之前和任何其它比较严重的内科或外科情况变化下应暂时停用几天。 肝脏作用 临床研究中，少数接受辛伐他汀治疗的成年患者出现血清转氨酶持续升高(高于正常值上限3倍)，这些患者间断或终止用药后，转氨酶水平通常缓慢地降低到治疗前水平。这种转氨酶升高不伴有黄疸或其它的症状体征，没有过敏的表现。这些患者中的一部分人在辛伐他汀治疗前肝功能检查异常和／或饮用过大量的酒精。 在北欧辛伐他汀生存研究中，整个研究期间有一种以上转氨酶升高超过正常值上限3倍的患者数，在辛伐他汀组和安慰剂组之间没有显著差异[14（0.7%）:12(0.6%)]。辛伐他汀组SGPT（ALT）单项升高达到正常值上限3倍的出现频率在研究的第一年中明显较高（20:8,P=0.023），但此后就不再明显。转氨酏的升高导致辛伐他汀治疗组（n=2221）中8名患者及安慰剂组（ n=2223）中5名患者停药。4S研究中，用辛伐他汀治疗的1986名患者在甚线时肝功能检查（ILFTs）正常，仅有8人（0.4％）在5.4年（中位随访期）中转氨酶连续超过正常值上限3倍和／或由于转氨酶升高而停药。此研究中所有患者辛伐他汀的起始剂量均为20mg，其中37％的患者在治疗过程中调整到40mg 。 在包括1105名患者的对照临床研究中，认为与药物有关的肝转氨酶持续升高6个月的发生率，在40mg和80mg剂量组分别为0.7％和1.8％。 在HPS研究中，20536名患者被随机分配服用辛伐他汀每日40mg或安慰剂。转氨酶升高超过正常值上限3倍的发生率在辛伐他汀组和安慰剂组分别为0.21％和0.09％。 建议在治疗开始前和随后的有临床指征时进行肝功能检查。对剂量调整到80mg的患者应在增量开始前。增量至 80mg后的3个月以及随后的第一年治疗中定期(比如半年)增加一次检查。应特别注意出现血清转氨酶升高的患者，对这些患者应及时重复测定并于此后增加肝功能检查的频率。如果转氨酶水平表现为上升趋势，尤其是转氨酶值上升到正常值上限3倍并持续不降时，应停药。 对饮用大量酒精和／或有既往肝脏病史的患者，应谨慎使用该药。辛伐他汀禁用于活动性肝脏疾病或原因不明的转氨酶升高的患者。 与其它降脂药一样，辛伐他汀治疗后有血清转氨酶中度(低于正常上限的3倍)升高的报道。这些变化在辛伐他汀治疗开始后很快出现。但往往是暂时的。不伴有任何症状并且不需要中断治疗。 眼科检查 即使在没有任何药物治疗时，随着年龄的增长晶状体混浊的发病率也会增加。长期临床研究资料显示，辛伐他汀对人的晶状体无不良影响。 贮藏 30℃以下保存。 Zocor 10 mg, film-coated tablets.Zocor 20 mg, film-coated ta 1. NAME OF THE MEDICINAL PRODUCT Zocor 10 mg, film-coated tablets. Zocor 20 mg, film-coated tablets. Zocor 40 mg, film-coated tablets. Zocor 80 mg, film-coated tablets. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 10 mg of simvastatin. Each tablet contains 20 mg of simvastatin. Each tablet contains 40 mg of simvastatin. Each tablet contains 80 mg of simvastatin. Excipient(s): For a full list of excipients, see section 6.1. Each 10 mg tablet contains 70.7 mg of lactose monohydrate. Each 20 mg tablet contains 141.5 mg of lactose monohydrate. Each 40 mg tablet contains 283.0 mg of lactose monohydrate. Each 80 mg tablet contains 565.8 mg of lactose monohydrate. 3. PHARMACEUTICAL FORM Film-coated tablet. The peach-coloured, oval-shaped tablets marked 'MSD 735' on one side contain 10 mg simvastatin. The tan-coloured, oval-shaped tablets marked 'MSD 740' on one side contain 20 mg simvastatin. The brick-red coloured, oval-shaped tablets marked 'MSD 749' on one side contain 40 mg simvastatin. The brick-red coloured, capsule-shaped tablets marked '543' on one side and '80' on the other contain 80 mg simvastatin. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Hypercholesterolaemia Treatment of primary hypercholesterolaemia or mixed dyslipidaemia, as an adjunct to diet, when response to diet and other non-pharmacological treatments (e.g. exercise, weight reduction) is inadequate. Treatment of homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are not appropriate. Cardiovascular prevention Reduction of cardiovascular mortality and morbidity in patients with manifest atherosclerotic cardiovascular disease or diabetes mellitus, with either normal or increased cholesterol levels, as an adjunct to correction of other risk factors and other cardioprotective therapy (see section 5.1). 4.2 Posology and method of administration The dosage range is 5-80 mg/day given orally as a single dose in the evening. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg/day given as a single dose in the evening. The 80-mg dose is only recommended in patients with severe hypercholesterolaemia and high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see sections 4.4 and 5.1). Hypercholesterolaemia The patient should be placed on a standard cholesterol-lowering diet, and should continue on this diet during treatment with Zocor. The usual starting dose is 10-20 mg/day given as a single dose in the evening. Patients who require a large reduction in LDL-C (more than 45 %) may be started at 20-40 mg/day given as a single dose in the evening. Adjustments of dosage, if required, should be made as specified above. Homozygous familial hypercholesterolaemia Based on the results of a controlled clinical study, the recommended dosage is Zocor 40 mg/day in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg. Zocor should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. Cardiovascular prevention The usual dose of Zocor is 20 to 40 mg/day given as a single dose in the evening in patients at high risk of coronary heart disease (CHD, with or without hyperlipidaemia). Drug therapy can be initiated simultaneously with diet and exercise. Adjustments of dosage, if required, should be made as specified above. Concomitant therapy Zocor is effective alone or in combination with bile acid sequestrants. Dosing should occur either > 2 hours before or > 4 hours after administration of a bile acid sequestrant. In patients taking ciclosporin, danazol, gemfibrozil, or other fibrates (except fenofibrate) concomitantly with Zocor, the dose of Zocor should not exceed 10 mg/day. In patients taking amiodarone or verapamil concomitantly with Zocor, the dose of Zocor should not exceed 20 mg/day. In patients taking diltiazem or amlodipine concomitantly with Zocor, the dose of Zocor should not exceed 40 mg/day. (See sections 4.4 and 4.5.) Dosage in renal insufficiency No modification of dosage should be necessary in patients with moderate renal insufficiency. In patients with severe renal insufficiency (creatinine clearance < 30 ml/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary, implemented cautiously. Use in the elderly No dosage adjustment is necessary. Use in children and adolescents (10-17 years of age) For children and adolescents (boys Tanner Stage II and above and girls who are at least one year post-menarche, 10-17 years of age) with heterozygous familial hypercholesterolaemia, the recommended usual starting dose is 10 mg once a day in the evening. Children and adolescents should be placed on a standard cholesterol-lowering diet before simvastatin treatment initiation; this diet should be continued during simvastatin treatment. The recommended dosing range is 10-40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy as recommended by the paediatric treatment recommendations (see sections 4.4 and 5.1). Adjustments should be made at intervals of 4 weeks or more. The experience of Zocor in pre-pubertal children is limited. 4.3 Contraindications • Hypersensitivity to simvastatin or to any of the excipients • Active liver disease or unexplained persistent elevations of serum transaminases • Pregnancy and lactation (see section 4.6) • Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone) (see section 4.5). 4.4 Special warnings and precautions for use Myopathy/Rhabdomyolysis Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with Zocor 24,747 (approximately 60 %) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03 %, 0.08 % and 0.61 % at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded. In a clinical trial in which patients with a history of myocardial infarction were treated with Zocor 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0 % compared with 0.02 % for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %. (See sections 4.8 and 5.1.) Creatine Kinase measurement Creatine Kinase (CK) should not be measured following strenuous exercise or in the presence of any plausible alternative cause of CK increase as this makes value interpretation difficult. If CK levels are significantly elevated at baseline (> 5 x ULN), levels should be re-measured within 5 to 7 days later to confirm the results. Before the treatment All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. Caution should be exercised in patients with pre-disposing factors for rhabdomyolysis. In order to establish a reference baseline value, a CK level should be measured before starting a treatment in the following situations: • Elderly (age  65 years) • Female gender • Renal impairment • Uncontrolled hypothyroidism • Personal or familial history of hereditary muscular disorders • Previous history of muscular toxicity with a statin or fibrate • Alcohol abuse. In such situations, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended. If a patient has previously experienced a muscle disorder on a fibrate or a statin, treatment with a different member of the class should only be initiated with caution. If CK levels are significantly elevated at baseline (> 5 x ULN), treatment should not be started. Whilst on treatment If muscle pain, weakness or cramps occur whilst a patient is receiving treatment with a statin, their CK levels should be measured. If these levels are found, in the absence of strenuous exercise, to be significantly elevated (> 5 x ULN), treatment should be stopped. If muscular symptoms are severe and cause daily discomfort, even if CK levels are < 5 x ULN, treatment discontinuation may be considered. If myopathy is suspected for any other reason, treatment should be discontinued. If symptoms resolve and CK levels return to normal, then re-introduction of the statin or introduction of an alternative statin may be considered at the lowest dose and with close monitoring. A higher rate of myopathy has been observed in patients titrated to the 80 mg dose (see section 5.1). Periodic CK measurements are recommended as they may be useful to identify subclinical cases of myopathy. However, there is no assurance that such monitoring will prevent myopathy. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes. Measures to reduce the risk of myopathy caused by medicinal product interactions (see also section 4.5) The risk of myopathy and rhabdomyolysis is significantly increased by concomitant use of simvastatin with potent inhibitors of CYP3A4 (such as itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), nefazodone), as well as gemfibrozil, ciclosporin, and danazol (see section 4.2). The risk of myopathy and rhabdomyolysis is also increased by concomitant use of other fibrates or by concomitant use of amiodarone or verapamil with higher doses of simvastatin (see sections 4.2 and 4.5). The risk is increased when by concomitant use of diltiazem or amlodipine with simvastatin 80 mg (see sections 4.2 and 4.5). The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of fusidic acid with statins (see section 4.5). Consequently, regarding CYP3A4 inhibitors, the use of simvastatin concomitantly with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated (see sections 4.3 and 4.5). If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Moreover, caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, ciclosporin, verapamil, diltiazem (see sections 4.2 and 4.5). Concomitant intake of grapefruit juice and simvastatin should be avoided. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin, danazol, or gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the combined use of simvastatin 10 mg daily with other fibrates (except fenofibrate), ciclosporin or danazol should be carefully weighed against the potential risks of these combinations. (See sections 4.2 and 4.5.) Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone. The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5). The combined use of simvastatin at doses higher than 40 mg daily with diltiazem or amlodipine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy (see sections 4.2 and 4.5). Rare cases of myopathy/rhabdomyolysis have been associated with concomitant administration of HMG-CoA reductase inhibitors and lipid-modifying doses ( 1 g/day) of niacin (nicotinic acid), either of which can cause myopathy when given alone. Physicians contemplating combined therapy with simvastatin and lipid-modifying doses ( 1 g/day) of niacin (nicotinic acid) or products containing niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and when the dose of either medicinal product is increased. In an interim analysis of an ongoing clinical outcomes study, an independent safety monitoring committee identified a higher than expected incidence of myopathy in Chinese patients taking simvastatin 40 mg and nicotinic acid/laropiprant 2000 mg/40 mg. Therefore, caution should be used when treating Chinese patients with simvastatin (particularly doses of 40 mg or higher) co-administered with lipid-modifying doses ( 1 g/day) of niacin (nicotinic acid) or products containing niacin. Because the risk of myopathy with statins is dose-related, the use of simvastatin 80 mg with lipid-modifying doses ( 1 g/day) of niacin (nicotinic acid) or products containing niacin is not recommended in Chinese patients. It is unknown whether there is an increased risk of myopathy in other Asian patients treated with simvastatin co-administered with lipid-modifying doses ( 1 g/day) of niacin (nicotinic acid) or products containing niacin. If the combination proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.5). Temporary suspension of simvastatin treatment may be considered. Hepatic effects In clinical studies, persistent increases (to > 3 x ULN) in serum transaminases have occurred in a few adult patients who received simvastatin. When simvastatin was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pre-treatment levels. It is recommended that liver function tests be performed before treatment begins and thereafter when clinically indicated. Patients titrated to the 80-mg dose should receive an additional test prior to titration, 3 months after titration to the 80-mg dose, and periodically thereafter (e.g., semi-annually) for the first year of treatment. Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3 x ULN and are persistent, simvastatin should be discontinued. The product should be used with caution in patients who consume substantial quantities of alcohol. As with other lipid-lowering agents, moderate (< 3 x ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and interruption of treatment was not required. Interstitial lung disease Cases of interstitial lung disease have been reported with some statins, including simvastatin, especially with long term therapy (see section 4.8). Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued. Use in children and adolescents (10-17 years of age ) Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolaemia have been eva luated in a controlled clinical trial in adolescent boys Tanner Stage II and above and in girls who were at least one year post-menarche. Patients treated with simvastatin had an adverse experience profile generally similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. (See sections 4.2, 4.8, and 5.1.) Adolescent females should be counselled on appropriate contraceptive methods while on simvastatin therapy (see sections 4.3 and 4.6). In patients aged < 18 years, efficacy and safety have not been studied for treatment periods > 48 weeks' duration and long-term effects on physical, intellectual, and sexual maturation are unknown. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-pubertal children and pre-menarchal girls. Excipient This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been performed in adults. Pharmacodynamic interactions Interactions with lipid-lowering medicinal products that can cause myopathy when given alone The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration with fibrates. Additionally, there is a pharmacokinetic interaction with gemfibrozil resulting in increased simvastatin plasma levels (see below Pharmacokinetic interactions and sections 4.2 and 4.4). When simvastatin and fenofibrate are given concomitantly, there is no evidence that the risk of myopathy exceeds the sum of the individual risks of each agent. Adequate pharmacovigilance and pharmacokinetic data are not available for other fibrates. Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses ( 1 g/day) of niacin (see section 4.4). Pharmacokinetic interactions Prescribing recommendations for interacting agents are summarized in the table below (further details are provided in the text; see also sections 4.2, 4.3, and 4.4). Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting agents Prescribing recommendations Potent CYP3A4 inhibitors: Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors (e.g. nelfinavir) Nefazodone   Contraindicated with simvastatin Gemfibrozil Avoid but if necessary, do not exceed 10 mg simvastatin daily Ciclosporin Danazol Other fibrates (except fenofibrate) Do not exceed 10 mg simvastatin daily Amiodarone Verapamil Do not exceed 20 mg simvastatin daily Diltiazem Amlodipine Do not exceed 40 mg simvastatin daily Fusidic acid Patients should be closely monitored. Temporary suspension of simvastatin treatment may be considered. Grapefruit juice Avoid grapefruit juice when taking simvastatin Effects of other medicinal products on simvastatin Interactions involving inhibitors of CYP3A4 Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), and nefazodone. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid. Therefore, combination with itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (e.g. nelfinavir), erythromycin, clarithromycin, telithromycin and nefazodone is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Caution should be exercised when combining simvastatin with certain other less potent CYP3A4 inhibitors: fluconazole, ciclosporin, verapamil or diltiazem (see sections 4.2 and 4.4). Fluconazole Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have been reported (see section 4.4). Ciclosporin The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin particularly with higher doses of simvastatin (see sections 4.2 and 4.4). Therefore, the dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with ciclosporin. Although the mechanism is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4. Danazol The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with higher doses of simvastatin (see sections 4.2 and 4.4). Gemfibrozil Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway (see sections 4.2 and 4.4). Amiodarone The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with higher doses of simvastatin (see section 4.4). In a clinical trial, myopathy was reported in 6 % of patients receiving simvastatin 80 mg and amiodarone. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with amiodarone, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis. Calcium Channel Blockers • Verapamil The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see section 4.4). In a pharmacokinetic study, concomitant administration with verapamil resulted in a 2.3-fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving concomitant medication with verapamil, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis. • Diltiazem The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see section 4.4). The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant diltiazem(see section 4.4). In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure of simvastatin acid, presumably due to inhibition of CYP3A4. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with diltiazem, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis. • Amlodipine Patients on amlodipine treated concomitantly with simvastatin 80 mg have an increased risk of myopathy. The risk of myopathy in patients taking simvastatin 40 mg was not increased by concomitant amlodipine. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of simvastatin should not exceed 40 mg daily in patients receiving concomitant medication with amlodipine, unless the clinical benefit is likely to outweigh the increased risk of myopathy and rhabdomyolysis. Niacin (nicotinic acid) Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses ( 1 g/day) of niacin (nicotinic acid). In a pharmacokinetic study, the co-administration of a single dose of nicotinic acid prolonged-release 2 g with simvastatin 20 mg resulted in a modest increase in the AUC of simvastatin and simvastatin acid and in the Cmax of simvastatin acid plasma concentrations. Fusidic acid The risk of myopathy may be increased by concomitant administration of fusidic acid with statins, including simvastatin. Isolated cases of rhabdomyolysis have been reported with simvastatin. Temporary suspension of simvastatin treatment may be considered. If it proves necessary, patients on fusidic acid and simvastatin should be closely monitored (see section 4.4). Grapefruit juice Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with simvastatin should therefore be avoided. Colchicine There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and simvastatin in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised. Rifampicin Because rifampicin is a potent CYP3A4 inducer, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of simvastatin. In a pharmacokinetic study in normal volunteers, the area under the plasma concentration curve (AUC) for simvastatin acid was decreased by 93% with concomitant administration of rifampicin. Effects of simvastatin on the pharmacokinetics of other medicinal products Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4. Oral anticoagulants In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. Very rare cases of elevated INR have been reported. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants 4.6 Pregnancy and lactation Pregnancy Zocor is contraindicated during pregnancy (see section 4.3). Safety in pregnant women has not been established. No controlled clinical trials with simvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors have been received. However, in an analysis of approximately 200 prospectively followed pregnancies exposed during the first trimester to Zocor or another closely related HMG-CoA reductase inhibitor, the incidence of congenital anomalies was comparable to that seen in the general population. This number of pregnancies was statistically sufficient to exclude a 2.5-fold or greater increase in congenital anomalies over the background incidence. Although there is no evidence that the incidence of congenital anomalies in offspring of patients taking Zocor or another closely related HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with Zocor may reduce the foetal levels of meva lonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia. For these reasons, Zocor must not be used in women who are pregnant, trying to become pregnant or suspect they are pregnant. Treatment with Zocor must be suspended for the duration of pregnancy or until it has been determined that the woman is not pregnant. (See sections 4.3 and 5.3.) Lactation It is not known whether simvastatin or its metabolites are excreted in human milk. Because many medicinal products are excreted in human milk and because of the potential for serious adverse reactions, women taking Zocor must not breast-feed their infants (see section 4.3). 4.7 Effects on ability to drive and use machines Zocor has no or negligible influence on the ability to drive and use machines. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported rarely in post-marketing experiences. 4.8 Undesirable effects The frequencies of the following adverse events, which have been reported during clinical studies and/or post-marketing use, are categorized based on an assessment of their incidence rates in large, long-term, placebo-controlled, clinical trials including HPS and 4S with 20,536 and 4,444 patients, respectively (see section 5.1). For HPS, only serious adverse events were recorded as well as myalgia, increases in serum transaminases and CK. For 4S, all the adverse events listed below were recorded. If the incidence rates on simvastatin were less than or similar to that of placebo in these trials, and there were similar reasonably causally related spontaneous report events, these adverse events are categorized as “rare”. In HPS (see section 5.1) involving 20,536 patients treated with 40 mg/day of Zocor (n = 10,269) or placebo (n = 10,267), the safety profiles were comparable between patients treated with Zocor 40 mg and patients treated with placebo over the mean 5 years of the study. Discontinuation rates due to side effects were comparable (4.8 % in patients treated with Zocor 40 mg compared with 5.1 % in patients treated with placebo). The incidence of myopathy was < 0.1 % in patients treated with Zocor 40 mg. Elevated transaminases (> 3 x ULN confirmed by repeat test) occurred in 0.21 % (n = 21) of patients treated with Zocor 40 mg compared with 0.09 % (n = 9) of patients treated with placebo. The frequencies of adverse events are ranked according to the following: Very common (> 1/10), Common ( 1/100, < 1/10), Uncommon ( 1/1000, < 1/100), Rare ( 1/10,000, < 1/1000), Very Rare (< 1/10,000), not known (cannot be estimated from the available data). Blood and lymphatic system disorders: Rare: anaemia Psychiatric disorders: Very rare: insomnia Not known: depression Nervous system disorders: Rare: headache, paresthesia, dizziness, peripheral neuropathy Very rare: memory impairment Respiratory, thoracic and mediastinal disorders: Not known: interstitial lung disease (see section 4.4) Gastrointestinal disorders: Rare: constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis Hepatobiliary disorders: Rare: hepatitis/jaundice Very rare: hepatic failure Skin and subcutaneous tissue disorders: Rare: rash, pruritus, alopecia Musculoskeletal and connective tissue disorders: Rare: myopathy* (including myositis), rhabdomyolysis with or without acute renal failure (see section 4.4), myalgia, muscle cramps * In a clinical trial, myopathy occurred commonly in patients treated with Zocor 80 mg/day compared to patients treated with 20 mg/day (1.0 % vs 0.02 %, respectively). Reproductive system and breast disorders: Not known: erectile dysfunction General disorders and administration site conditions: Rare: asthenia An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: angioedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, ESR increased, arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea and malaise. Investigations: Rare: increases in serum transaminases (alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase) (see section 4.4 Hepatic effects), elevated alkaline phosphatase; increase in serum CK levels (see section 4.4). The following additional adverse events have been reported with some statins: • sleep disturbances, including nightmares • memory loss • sexual dysfunction. Children and adolescents (10-17 years of age) In a 48-week study involving children and adolescents (boys Tanner Stage II and above and girls who were at least one year post-menarche) 10-17 years of age with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile of the group treated with Zocor was generally similar to that of the group treated with placebo. The long-term effects on physical, intellectual, and sexual maturation are unknown. No sufficient data are currently available after one year of treatment. (See sections 4.2, 4.4, and 5.1.) 4.9 Overdose To date, a few cases of overdosage have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. There is no specific treatment in the event of overdose. In this case, symptomatic and supportive measures should be adopted. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: HMG-CoA reductase inhibitor ATC-Code: C10A A01 After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to the corresponding active beta-hydroxyacid form which has a potent activity in inhibiting HMG-CoA reductase (3 hydroxy – 3 methylglutaryl CoA reductase). This enzyme catalyses the conversion of HMG-CoA to meva lonate, an early and rate-limiting step in the biosynthesis of cholesterol. Zocor has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density protein (VLDL) and is catabolised predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of Zocor may involve both reduction of VLDL-cholesterol (VLDL-C) concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with Zocor. In addition, Zocor moderately increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total- to HDL-C and LDL- to HDL-C are reduced. High Risk of Coronary Heart Disease (CHD) or Existing Coronary Heart Disease In the Heart Protection Study (HPS), the effects of therapy with Zocor were assessed in 20,536 patients (age 40-80 years), with or without hyperlipidaemia, and with coronary heart disease, other occlusive arterial disease or diabetes mellitus. In this study, 10,269 patients were treated with Zocor 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33 %) had LDL-C levels below 116 mg/dL; 5,063 patients (25 %) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42 %) had levels greater than 135 mg/dL. Treatment with Zocor 40 mg/day compared with placebo significantly reduced the risk of all cause mortality (1328 [12.9 %] for simvastatin-treated patients versus 1507 [14.7 %] for patients given placebo; p = 0.0003), due to an 18 % reduction in coronary death rate (587 [5.7 %] versus 707 [6.9 %]; p = 0.0005; absolute risk reduction of 1.2 %). The reduction in non-vascular deaths did not reach statistical significance. Zocor also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27 % (p < 0.0001). Zocor reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other non-coronary revascularization procedures by 30 % (p < 0.0001) and 16 % (p = 0.006), respectively. Zocor reduced the risk of stroke by 25 % (p < 0.0001), attributable to a 30 % reduction in ischemic stroke (p < 0.0001). In addition, within the subgroup of patients with diabetes, Zocor reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21 % (p = 0.0293). The proportional reduction in event rate was similar in each subgroup of patients studied, including those without coronary disease but who had cerebrovascular or peripheral artery disease, men and women, those aged either under or over 70 years at entry into the study, presence or absence of hypertension, and notably those with LDL cholesterol below 3.0 mmol/l at inclusion. In the Scandinavian Simvastatin Survival Study (4S), the effect of therapy with Zocor on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomised, double-blind, placebo-controlled study, patients with angina or a previous myocardial infarction (MI) were treated with diet, standard care, and either Zocor 20-40 mg/day (n = 2,221) or placebo (n = 2,223) for a median duration of 5.4 years. Zocor reduced the risk of death by 30 % (absolute risk reduction of 3.3 %). The risk of CHD death was reduced by 42 % (absolute risk reduction of 3.5 %). Zocor also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent nonfatal MI) by 34 %. Furthermore, Zocor significantly reduced the risk of fatal plus nonfatal cerebrovascular events (stroke and transient ischemic attacks) by 28 %. There was no statistically significant difference between groups in non-cardiovascular mortality. The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) eva luated the effect of treatment with Zocor 80 mg versus 20 mg (median follow-up 6.7 yrs) on major vascular events (MVEs; defined as fatal CHD, non-fatal MI, coronary revascularization procedure, non-fatal or fatal stroke, or peripheral revascularization procedure) in 12,064 patients with a history of myocardial infarction. There was no significant difference in the incidence of MVEs between the 2 groups; Zocor 20 mg (n = 1553; 25.7 %) vs. Zocor 80 mg (n = 1477; 24.5 %); RR 0.94, 95 % CI: 0.88 to 1.01. The absolute difference in LDL-C between the two groups over the course of the study was 0.35 ± 0.01 mmol/L. The safety profiles were similar between the two treatment groups except that the incidence of myopathy was approximately 1.0 % for patients on Zocor 80 mg compared with 0.02 % for patients on 20 mg. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1 %. Primary Hypercholesterolaemia and Combined Hyperlipidaemia In studies comparing the efficacy and safety of simvastatin 10, 20, 40 and 80 mg daily in patients with hypercholesterolemia, the mean reductions of LDL-C were 30, 38, 41 and 47 %, respectively. In studies of patients with combined (mixed) hyperlipidaemia on simvastatin 40 mg and 80 mg, the median reductions in triglycerides were 28 and 33 % (placebo: 2 %), respectively, and mean increases in HDL-C were 13 and 16 % (placebo: 3 %), respectively. Clinical Studies in Children and Adolescents (10-17 years of age) In a double-blind, placebo-controlled study, 175 patients (99 boys Tanner Stage II and above and 76 girls who were at least one year post-menarche) 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolaemia (heFH) were randomized to simvastatin or placebo for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level > 189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy and received simvastatin 40 mg or placebo. Zocor significantly decreased plasma levels of LDL-C, TG, and Apo B. Results from the extension at 48 weeks were comparable to those observed in the base study. After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0-289.0 mg/dL) in the Zocor 40 mg group compared to 207.8 mg/dL (range: 128.0-334.0 mg/dL) in the placebo group. After 24 weeks of simvastatin treatment (with dosages increasing from 10, 20 and up to 40 mg daily at 8- week intervals), Zocor decreased the mean LDL-C by 36.8 % (placebo: 1.1 % increase from baseline), Apo B by 32.4 % (placebo: 0.5 %), and median TG levels by 7.9 % (placebo: 3.2 %) and increased mean HDL-C levels by 8.3 % (placebo: 3.6 %). The long-term benefits of Zocor on cardiovascular events in children with heFH are unknown. The safety and efficacy of doses above 40 mg daily have not been studied in children with heterozygous familial hypercholesterolaemia. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. 5.2 Pharmacokinetic properties Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis takes place mainly in the liver; the rate of hydrolysis in human plasma is very slow. The pharmacokinetic properties have been eva luated in adults. Pharmacokinetic data in children and adolescents are not available. Absorption In man simvastatin is well absorbed and undergoes extensive hepatic first-pass extraction. The extraction in the liver is dependent on the hepatic blood flow. The liver is the primary site of action of the active form. The availability of the beta-hydroxyacid to the systemic circulation following an oral dose of simvastatin was found to be less than 5 % of the dose. Maximum plasma concentration of active inhibitors is reached approximately 1-2 hours after administration of simvastatin. Concomitant food intake does not affect the absorption. The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of medicinal product occurred after multiple dosing. Distribution The protein binding of simvastatin and its active metabolite is > 95 %. Elimination Simvastatin is a substrate of CYP3A4 (see sections 4.3 and 4.5). The major metabolites of simvastatin present in human plasma are the beta-hydroxyacid and four additional active metabolites. Following an oral dose of radioactive simvastatin to man, 13 % of the radioactivity was excreted in the urine and 60 % in the faeces within 96 hours. The amount recovered in the faeces represents absorbed medicinal product equivalents excreted in bile as well as unabsorbed medicinal product. Following an intravenous injection of the beta-hydroxyacid metabolite, its half-life averaged 1.9 hours. An average of only 0.3 % of the IV dose was excreted in urine as inhibitors. 5.3 Preclinical safety data Based on conventional animal studies regarding pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity, there are no other risks for the patient than may be expected on account of the pharmacological mechanism. At maximally tolerated doses in both the rat and the rabbit, simvastatin produced no foetal malformations, and had no effects on fertility, reproductive function or neonatal development. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core butylated hydroxyanisole (E320) ascorbic acid (E300) citric acid monohydrate (E330) microcrystalline cellulose (E460) pregelatinized starch magnesium stearate (E572) lactose monohydrate Tablet coating hypromellose (E464) hydroxypropylcellulose (E463) titanium dioxide (E171) talc (E553b) yellow iron oxide (E172) (10 and 20 mg tablets) red iron oxide (E172) (10, 20, 40, and 80 mg tablets) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Do not store above 25°C. Keep blister in outer carton in order to protect from moisture. 6.5 Nature and contents of container Zocor 10 mg Blister packages of a trilaminate film composed of polyvinyl chloride (PVC)/Polyethylene (PE)/Polyvinylidine chloride (PVDC) with aluminum foil lidding in packs of 1, 4, 10, 14, 15, 20, 28, 30, 50, 60, 98, or 100 tablets. Blister packages composed of polyvinyl chloride (PVC) with aluminum foil lidding in packs of 4, 10, or 28, or 30 tablets. Amber glass bottles with metal closures in packs of 30 or 50 tablets. Polypropylene bottles in packs of 50 tablets. High Density Polyethylene (HDPE) bottles in packs of 30, 50 or 100 tablets. Unit dose blisters containing the trilaminate film composed of polyvinyl chloride (PVC)/Polyethylene (PE)/Polyvinylidine chloride (PVDC) with aluminum foil lidding in packs of 49 or 500 tablets. Zocor 20 mg Blister packages of a trilaminate film composed of polyvinyl chloride (PVC)/Polyethylene (PE)/Polyvinylidine chloride (PVDC) with aluminum foil lidding in packs of 1, 4, 10, 14, 15, 20, 28, 30, 50, 56, 60, 84, 90, 98, 100, or 168 tablets. Blister packages composed of polyvinyl chloride (PVC) with aluminum foil lidding in packs of 14, 28, 30, 50, or 90 tablets. Amber glass bottles with metal closures in packs of 30 or 50 tablets. Polypropylene bottles in packs of 50 tablets. High Density Polyethylene (HDPE) bottles in packs of 30, 50 or 100 tablets. Unit dose blisters containing the trilaminate film composed of polyvinyl chloride (PVC)/Polyethylene (PE)/Polyvinylidine chloride (PVDC) with aluminum foil lidding in packs of 28, 49, 84, 98, or 100 tablets. Zocor 40mg Blister packages of a trilaminate film composed of polyvinyl chloride (PVC)/Polyethylene (PE)/Polyvinylidine chloride (PVDC) with aluminum foil lidding in packs of 1, 4, 7, 10, 14, 15, 20, 28, 30, 49, 50, 56, 60, 84, 90, 98, 100, or 168 tablets. Blister packages composed of polyvinyl chloride (PVC) with aluminum foil lidding in packs of 7, 14, 28, 30, 49, 50, or 90 tablets. Amber glass bottles with metal closures in packs of 30 or 50 tablets. Polypropylene bottles in packs of 50 tablets. High Density Polyethylene (HDPE) bottles in packs of 30, 50 or 100 tablets. Unit dose blisters containing the trilaminate film composed of polyvinyl chloride (PVC)/Polyethylene (PE)/Polyvinylidine chloride (PVDC) with aluminum foil lidding in packs of 28, 49, 98, or 100 tablets. Zocor 80 mg Blister packages of a trilaminate film composed of polyvinyl chloride (PVC)/Polyethylene (PE)/Polyvinylidine chloride (PVDC) with aluminum foil lidding in packs of 7, 10, 14, 20, 28, 30, 49, 50, 56, 98, or 100 tablets. High Density Polyethylene (HDPE) bottles in packs of 100 tablets. Unit dose blisters containing the trilaminate film composed of polyvinyl chloride (PVC)/Polyethylene (PE)/Polyvinylidine chloride (PVDC) with aluminum foil lidding in packs of 28, 49, 56, or 98 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. 7. MARKETING AUTHORISATION HOLDER Merck Sharp & Dohme Ireland (Human Health) Limited Pelham House South County Business Park Leopardstown Dublin 18 Ireland 8. MARKETING AUTHORISATION NUMBER(S) 10 mg Tablet: PA 1286/22/2 20 mg Tablet: PA 1286/22/3 40 mg Tablet: PA 1286/22/4 80 mg Tablet: PA 1286/22/5 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Licence first granted 10 November 1989. Last renewed 10 March 2009 10. DATE OF REVISION OF THE TEXT February 2011