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英文药名: Renagel(Sevelamer Tablets) 中文药名: 磷能解, 司维拉姆片 生产厂家: Genzyme Corporation
Titration and maintenance Serum phosphate levels should be closely monitored and the dose of Renagel adjusted accordingly with the goal of lowering serum phosphate to 1.76 mmol/l (5.5 mg/dl) or less. Serum phosphate should be tested every two to three weeks until a stable serum phosphate level is reached and on a regular basis thereafter. The dose range may vary between 1 and 5 tablets of 800 mg per meal. The average actual daily dose used in the chronic phase of a one year clinical study was 7 grams of sevelamer. Paediatric population The safety and efficacy of this product has not been established in patients below the age of 18 years. Renagel is not recommended in children below the age of 18 years. Renal impairment The safety and efficacy of this product has not been established in predialysis patients. Renagel is not recommended in these patients. Method of administration For oral use Patients should take Renagel with meals and adhere to their prescribed diets. The tablets must be swallowed whole. Do not chew. 4.3 Contraindications • Hypersensitivity to sevelamer or to any of the excipients listed in section 6.1. • Hypophosphataemia • Bowel obstruction. 4.4 Special warnings and precautions for use Efficacy and safety of Renagel has not been studied in patients with: • swallowing disorders • active inflammatory bowel disease • gastrointestinal motility disorders including untreated or severe gastroparesis, diverticulosis, retention of gastric contents and abnormal or irregular bowel motion • patients with a history of major gastrointestinal surgery Therefore caution should be exercised when Renagel is used in patients with these disorders. Intestinal obstruction and ileus/subileus In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment with Renagel. Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with Renagel. Renagel treatment should be re-evaluated in patients who develop severe constipation or other severe gastrointestinal symptoms. Fat-soluble vitamins Depending on diet intake and the nature of end stage renal failure, dialysis patients may develop low vitamin A, D, E and K levels. It cannot be excluded that Renagel can bind fat-soluble vitamins contained in ingested food. Therefore, in patients not taking these vitamins, monitoring vitamin A, D and E levels and assessing vitamin K status through the measurement of thromboplastin time should be considered and the vitamins should be supplemented if necessary. Additional monitoring of vitamins and folic acid is recommended in patients receiving peritoneal dialysis, since in the clinical study, vitamin A, D, E and K levels were not measured in these patients. Folate deficiency There is at present insufficient data to exclude the possibility of folate deficiency during long term Renagel treatment. Hypocalcaemia/hypercalcaemia Patients with renal insufficiency may develop hypocalcaemia or hypercalcaemia. Renagel does not contain calcium. Serum calcium levels should be monitored as is done in normal follow-up of a dialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia. Metabolic acidosis Patients with chronic renal failure are predisposed to developing metabolic acidosis. Worsening of acidosis has been reported upon switching from other phosphate binders to sevelamer in a number of studies where lower bicarbonate levels in the sevelamer-treated patients compared to patients treated with calcium-based binders were observed. Closer monitoring of serum bicarbonate levels is therefore recommended. Peritonitis Patients receiving dialysis are subject to certain risks for infection specific to the dialysis modality. Peritonitis is a known complication in patients receiving peritoneal dialysis (PD) and in a clinical study with Renagel, a number of peritonitis cases were reported. Therefore, patients on PD should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis. Swallowing and choking difficulties Uncommon reports of difficulty swallowing the Renagel tablet have been reported. Many of these cases involved patients with co-morbid conditions including swallowing disorders or oroesophageal abnormalities. Caution should be exercised when Renagel is used in patients with difficulty swallowing. Anti-arrhythmic and anti-seizure medicinal products Caution should be exercised when prescribing Renagel to patients also taking anti-arrhythmias and anti-seizure medicinal products (see section 4.5). Hypothyroidism Closer monitoring of patients with hypothyroidism co-administered with sevelamer hydrochloride and levothryroxine is recommended (see section 4.5). Long term chronic treatment As data on the chronic use of sevelamer for over one year are not yet available, potential absorption and accumulation of sevelamer during long-term chronic treatment cannot be totally excluded (see section 5.2 Pharmacokinetics). Hyperparathyroidism Renagel alone is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25 - dihydroxy Vitamin D3 or one of its analogues to lower the intact parathyroid hormone (iPTH) levels. Serum chloride Serum chloride may increase during Renagel treatment as chloride may be exchanged for phosphorus in the intestinal lumen. Although no clinically significant serum chloride increase has been observed in the clinical studies, serum chloride should be monitored as is done in the routine follow-up of a dialysis patient. One gram of Renagel contains approximately 180 mg (5.1mEq) chloride. 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have not been conducted in patients on dialysis. In interaction studies in healthy volunteers, Renagel decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with Renagel in a single dose study. Consequently, Renagel should not be taken simultaneously with ciprofloxacin. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from clinical trials. Caution should be exercised when prescribing Renagel to patients also taking these medications. During post marketing experience, very rare cases of increased TSH levels have been reported in patients co-administered Renagel and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medications. Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus have been reported in transplant patients when coadministered with Renagel without any clinical consequences (i.e graft rejection). The possibility of an interaction cannot be excluded and a close monitoring of blood concentrations of mycophenolate mofetil, ciclosporin and tacrolimus should be considered during the use of combination and after its withdrawal. In interaction studies in healthy volunteers, Renagel had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol. Renagel is not absorbed and may affect the bioavailability of other medicinal products. When administering any medicinal product where a reduction in the bioavailability could have a clinically significant effect on safety or efficacy, the medicinal product should be administered at least one hour before or three hours after Renagel, or the physician should consider monitoring blood levels. 4.6 Fertility, pregnancy and lactation Pregnancy The safety of Renagel has not been established in pregnant women. In animal studies there was no evidence that sevelamer induced embryo-foetal toxicity. Renagel should only be given to pregnant women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the foetus (See 5.3 Preclinical safety data). Breast-feeding The safety of Renagel has not been established in lactating women. Renagel should only be given to lactating women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the infant (See 5.3 Preclinical safety data). Fertility There are no data from the effect of sevelamer on fertility in humans. Studies in animals have shown that sevelamer did not impair fertility in male or female rats at exposures at a human equivalent dose 2 times the maximum clinical trial dose of 13 g/day. 4.7 Effects on ability to drive and use machines No studies on the effects on ability to drive and use machines have been performed. 4.8 Undesirable effects In parallel design studies involving 244 haemodialysis patients with treatment duration of up to 54 weeks and 97 peritoneal dialysis patients with treatment duration of 12 weeks, the most frequently occurring (≥ 5% of patients) adverse reactions possibly or probably related to Renagel were all in the gastrointestinal disorders system organ class. Adverse reactions from these studies (299 patients) and from uncontrolled clinical trials (384 patients) are listed by frequency in the table below. The reporting rate is classified as very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), not known (cannot be estimated form the available data).
4.9 Overdose No case of overdose has been reported. Renagel has been given to normal healthy volunteers in doses up to 14 grams, the equivalent of seventeen 800 mg tablets, per day for eight days with no undesirable effects. 5. Pharmacological properties 5.1 Pharmacodynamic properties Treatment of hyperphosphatemia. ATC code: V03AE02. Renagel contains sevelamer, a non-absorbed phosphate binding poly(allylamine hydrochloride) polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines become partially protonated in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract, sevelamer lowers the phosphate concentration in the serum. In clinical trials, sevelamer has been shown to be effective in reducing serum phosphorus in patients receiving haemodialysis or peritoneal dialysis. Sevelamer decreases the incidence of hypercalcaemic episodes as compared to patients using calcium based phosphate binders alone, probably because the product itself does not contain calcium. The effects on phosphate and calcium were proven to be maintained throughout a study with one year follow-up. Sevelamer has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. In clinical trials mean total and LDL cholesterol declined by 15-31%. This effect is observed after 2 weeks is maintained with long-term treatment. Triglycerides, HDL cholesterol and albumin did not change. In the clinical studies in haemodialysis patients, sevelamer alone did not have a consistent and clinically significant effect on serum intact parathyroid hormone (iPTH). In the 12 week study involving peritoneal dialysis patients however, similar iPTH reductions were seen compared with patients receiving calcium acetate. In patients with secondary hyperparathyroidism Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25 - dihydroxy Vitamin D3 or one of its analogues to lower the intact parathyroid hormone (iPTH) levels. In a clinical trial of one-year duration, Renagel had no adverse effect on bone turnover or mineralisation compared to calcium carbonate. 5.2 Pharmacokinetic properties Renagel is not absorbed from the gastrointestinal tract according to a single dose pharmacokinetic study in healthy volunteers. Pharmacokinetic studies have not been carried out in renal failure patients (see section 4.4 Special warnings and special precautions for use). 5.3 Preclinical safety data In preclinical studies in rats and dogs, Renagel at a dose of 10 times the maximum human doses reduced absorption of fat soluble vitamins D, E and K, and folic acid. In a study in rats, administering sevelamer in 15-30 x the human dose, an increase in serum copper was detected. This was not confirmed in a dog study or in clinical trials. Currently, no formal carcinogenicity data are available. However, in vitro and in vivo studies have indicated that Renagel does not have genotoxic potential. Also the medicinal product is not absorbed in the gastrointestinal tract. In reproduction studies there was no evidence that sevelamer induced embryolethality, foetotoxicity or teratogenicity at the doses tested (up to 1 g/kg/day in rabbits and up to 4.5 g/kg/day in rats). Deficits in skeletal ossification were observed in several locations in fetuses of female rats dosed with sevelamer at 8-20 times the maximum human dose of 200 mg/kg. The effects may be secondary to vitamin D and/or vitamin K depletion at these high doses. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core: Silica, colloidal anhydrous Stearic acid Film-coating: Hypromellose Diacetylated monoglycerides Printing ink: Iron oxide black (E172) Propylene glycol Hypromellose 6.2 Incompatibilities Not applicable 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not store above 25ºC. Keep the bottle tightly closed in order to protect from moisture. 6.5 Nature and contents of container HDPE bottles, with a child resistant polypropylene cap and a foil induction seal. Package sizes are: 6 bottles of 30 tablets 1bottle of 100 tablets 1 bottle of 180 tablets 2 bottles of 180 tablets 3 bottles of 180 tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands 8. Marketing authorisation number(s) EU/1/99/123/008 EU/1/99/123/009 EU/1/99/123/010 EU/1/99/123/011 EU/1/99/123/012 EU/1/99/123/013 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 28 January, 2000 Date of latest renewal: 02 February 2010 10. Date of revision of the text 12/2011 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/. 美国食品和药品管理局（Food and Drug Administration）FDA批准Genzyme Generals 和GelTex两家制药公司生产Renagel片剂，用于治疗行血液透析的晚期肾病患者的高血磷症。 FDA批准Genzyme Generals 和GelTex两家制药公司生产Renagel片剂，用于治疗行血液透析的晚期肾病患者的高血磷症。据FDA周四发表的声明称，预计在今年下半年市场上开始出售800 mg 和400 mg两种剂量的片剂。Genzyme General公司发言人指出，“为了使临床医生选择余地更大，目前的403 mg胶囊剂型仍将继续销售。” 两家公司称，“400mg 片剂比目前的胶囊小得多，同时800mg片剂适用于那些需要大剂量，又不愿服用太多药丸的患者。” Renagel于1998年年底投入使用，在美国的销售额去年达到两千万美圆。Genzyme General公司期望其销售额在2000年翻一番，部分地反映出该药试图进入国际市场的愿望。该公司发言人强调，2000年第一季度，该药销售额总值为八百万美圆，主要是来自美国市场。 除了美国，Renagel胶囊正在欧洲，加拿大和以色列广泛使用。Genzyme公司于今年第一季度向欧洲申请批准生产Renagel片剂，并拟在第三季度向加拿大申请批准片剂生产。 该药品的潜在市场包括有美国每年行透析的280,000名晚期肾病患者和170,000欧洲透析患者，而且每年该数字以大约7%的幅度增长。 Renagel可在消化道和正常消化过程结合并除去饮食中的磷，血磷水平升高可能导致行血液透析的病人出现致命的并发症。 透析病人血磷控制的新药介绍 － Renagel 由于药物使用的习惯与重症照护的进步，使得台湾地区长期透析病友的人数居高不下，其发生率已在全世界中名列前茅。现有约4万名的长期洗肾病友，每年更新增加六至七千名这方面病患。肾友长期并发症的处理，尤其是慢性肾衰竭病人钙磷代谢异常的治疗，已经是肾脏医学界的一项不可忽视的课题。 钙和磷在正常人体内保持精密的平衡，它们都在肾脏、骨骼和内分泌系统的严格控制下，依据人体的需要来吸收、排除与流动。而骨骼就是扮演一个巨大又可交换的钙磷贮藏处，也是这些矿物质的提供和缓冲处。而慢性肾衰竭病人钙磷的平衡已经受到严重破坏和影响，因为饮食中的磷无法避免地吸收到体内，体内的磷酸盐又不能有效排除，使得血中磷酸盐过多常常会有高磷血症的问题。以美国为例，血液中磷值高 (血磷值大于5.0mg/dL) 的患者约占所有洗肾病人的70%。进一步分析则发现，血磷值大于6.5mg/dL的患者约占所有洗肾病人的39%，这些患者相对于血磷值正常者，其死亡率风险值则高出约27%。原因可能是高磷血症的患者长久会有多种并发症：包括次发性副甲状腺机能亢进症、肾性骨病变、软组织钙化等。由于磷酸盐是由饮食从小肠被吸收到人体，所以饮食控制是降低血磷值的最基本方法。透析也是另外一种降低血磷值的方法。但不论是使用饮食控制或是透析，大部份的病患 (90-95%) 仍必须服用磷结合剂来控制高磷血症。 目前市面上所使用的磷结合剂内，铝氢氧化物是一个较强的磷结合药物，但此类药物有一些严重的副作用如骨病变、贫血和老年失智症之类的脑神经病变，所以已在很多先进国家禁止使用。这些病人都需要磷结合剂来治疗。含钙的磷结合剂像是碳酸钙或醋酸钙，在近十年来成为主流。然而，服用大量的碳酸钙或醋酸钙当磷结合剂，所引发的一个重要问题是血液中钙的浓度增加，甚至产生了高血钙症，亦即血钙值高于10.5mg/dL。目前我国长期洗肾病患中，每五个人就有一人具高血钙症。长期高血钙将会增加血管钙化和心血管疾病的危险率例如心肺衰竭、心肌梗塞、心绞痛、心律不整甚至减少末期肾病变病患者的存活率。所以高血钙副作用及心血管或软组织的钙化已造成使用含钙的磷结合剂的限制，并且是激发世界各地的学者寻找新一代磷结合剂的重要原因。 在新一代磷结合剂的发展上，1998年美国食品卫生检验局 (Food and Drug Administration; FDA) 核准上市的新一代的药品Renagel ﹝sevelamer hydrochloride﹞，是一个相当重要的里程碑。Renagel在药理分类上是全新的药物，其特色为不含铝、不含钙、亦不含任何金属成份的聚分子化合物，病人在三餐同时与药物并服，它以类似树脂交换离子方式吸附肠道中的磷酸，结合后再由粪便排出体外。由于Renagel无全身性吸收，所以安全性高，可以有效控制血磷值并且不会导致高血钙症等副作用。磷能解锭的使用禁忌，主要是对低血磷、大肠阻塞、以及对该药成份会过敏的患者。 长期洗肾的病友，还需考虑软组织钙化，尤其是动脉钙化问题，这可能与心脏血管疾病有密切关联。Braun等人在二年的长期临床试验中，研究了114位洗肾病友，发现Renagel与其它含钙制剂的降磷效果相当。但使用含钙制剂的病人，有明显较多的高钙血症与PTH的过度抑制现象。其中高钙血症 (Ca ＞2.8 mmol/L) 在含钙制剂组与Renagel治疗组的出现比例，分别是19%与0%。另一方面，使用含钙制剂的病人，其心血管钙化程度有明显的增加 (median +34% in coronary artery)， 而服用Renagel的肾友则未观察到这个问题。 目前Renagel已在美、日、加、与欧洲等共计40多国上市并广泛的使用。在我国，Renagel已在林口及台北长庚完成国内人体临床试验，并发表于2003年台湾肾脏医学会年会。试验结果看来，肾友在10周的试验期服用此药可以有效降低血磷值，而且高血钙症的副作用明显低于服用钙剂患者。卫生署已核发该药品上市许可证。预期Renagel将在今年2005年8月在台湾正式上市。 -------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: renagel 400mg/tab 360tabs/bottle 原产地英文药品名: sevelamer hydrochloride 中文参考商品译名: 磷能解 400毫克/片 360片/瓶 中文参考药品译名: 盐酸司维拉姆 生产厂家中文参考译名: 健赞 生产厂家英文名: Genzyme -------------------------------------------------------------- 产地国家: 美国 原产地英文商品名: renagel 800mg/tab 180tabs/bottle 原产地英文药品名: sevelamer hydrochloride 中文参考商品译名: 磷能解 800毫克/片 180片/瓶 中文参考药品译名: 盐酸司维拉姆 生产厂家中文参考译名: 健赞 生产厂家英文名: Genzyme |
