英文药名: Renagel (Sevelamer Tablets) 中文药名: 司维拉姆片,磷能解 需要处方购买 生产厂家: Genzyme Corporation 药品介绍 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，“400 mg 片剂比目前的胶囊小得多，同时800 mg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。 处方信息摘要 这些亮点不包括所有需要使用Renagel安全和有效的信息。查看完整的处方信息Renagel。 Renagel（磷能解盐酸盐）片剂用于口腔 美国初始认证：2000 适应症 Renagel ®是一种磷酸盐粘结剂的血清磷与透析慢性肾脏疾病患者的对照说明。 剂量和用法 起始剂量是800毫克一个或两个或三个两到四个次，每次400毫克，每日随餐服用药片。 每餐一两片调整一周需要获得血清磷的目标区间。  剂型和优势 片剂：800毫克和400毫克 禁忌 在与肠梗阻患者。 注意事项： 的安全性和疗效Renagel患者吞咽困难，吞咽障碍，严重的胃肠运动障碍包括严重便秘，胃肠道手术或重大尚未确定。应谨慎行事时Renagel是胃肠道疾病与这些病人使用。 不良反应 对停止治疗的最常见的原因是胃肠道不良反应。 在并行设计研究，为期12周，治疗中出现的不良反应，腹膜透析患者Renagel片包括消化不良（12％），腹膜炎（8％），腹泻（5％），恶心（5％），便秘（4 ％），皮肤瘙痒（4％），腹胀（3％），呕吐（3％），疲劳（3％），厌食（3％）和关节痛（3％）。  以类似的速度类似的反应发生在血液透析和腹膜透析患者。 粪便嵌塞和不太常用，肠梗阻，肠阻塞，肠穿孔的病例报告。 药物相互作用 跌幅约50％的环丙沙星的生物利用度。  在正常志愿者研究，磷能解组并没有改变的地高辛，华法令，依那普利，美托洛尔，铁单剂量药代动力学。  当管理的口服药物凡在该药物的生物利用度减少会对它的安全性或疗效临床疗效显着，药物应给予至少一小时前或后3 Renagel小时，或医师应考虑监测血药浓度该药物。  RENAGEL® sevelamer hydrochloride - 800 mg tablets NAME OF THE MEDICINE RENAGEL® (sevelamer hydrochloride) 800 mg tablets. The structure is represented in Figure 1. The CAS registry number for sevelamer hydrochloride is [152751-57-0]. Figure 1: Structure of Sevelamer Hydrochloride a, b = number of primary amine groups a + b = 9 c = number of crosslinking groups c = 1 n = fraction of protonated amines n = 0.4 m = large number to indicate extended polymer network The primary amine groups shown in the structure are derived directly from poly(allylamine hydrochloride). The cross-linking groups consist of two secondary amine groups derived from poly(allylamine hydrochloride) and one molecule of epichlorohydrin. DESCRIPTION Sevelamer, or poly(allyamine-co-N,N'-diallyl-1,3-diamino-2-hydroxypropane), a cross-linked polymer, is a white to off-white, water insoluble powder. Sevelamer is a partial hydrochloride salt, approximately 40 % amine hydrochloride and 60 % free base. Sevelamer hydrochloride is hydrophilic, but also insoluble in water. RENAGEL tablets contain 800 mg of the active ingredient sevelamer hydrochloride on an anhydrous basis. RENAGEL tablets are oval film coated tablets imprinted with "RENAGEL 800" on the crown, single side. The imprint contains iron oxide black ink, propylene glycol and isopropyl alcohol. The inactive ingredients in RENAGEL tablets are hypromellose, diacetylated monoglycerides, colloidal anhydrous silica and stearic acid. PHARMACOLOGY Pharmacokinetics A mass balance study using 14C-sevelamer hydrochloride in 16 healthy male and female volunteers showed that sevelamer is not systemically absorbed. No absorption studies have been performed in patients with renal disease. Pharmacodynamics Patients with end-stage renal disease (ESRD) retain phosphorus and can develop hyperphosphataemia. 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 phosphorus molecules through ionic and hydrogen bonding. By binding phosphorus in the dietary tract, sevelamer lowers the phosphorus concentration in the serum. RENAGEL 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. RENAGEL treatment also results in a lowering of low-density lipoprotein (LDL) and total serum cholesterol levels by increasing faecal excretion of bile acids. High serum phosphorus can precipitate serum calcium resulting in ectopic calcification. When the product of serum calcium and phosphorus concentrations (Ca x P) exceeds 4.46 (mmol/L)2, there is an increased risk that ectopic calcification will occur. Hyperphosphataemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency. An increase in parathyroid hormone (PTH) levels is characteristic of patients with chronic renal failure. Increased levels of PTH can lead to the bone disease osteitis fibrosa. A decrease in serum phosphorus may decrease serum PTH levels. CLINICAL TRIALS In vitro studies have shown that the capsule and tablet formulations bind phosphate to a similar extent. Since RENAGEL does not contain aluminium, it does not cause aluminium intoxication. The ability of RENAGEL to lower serum phosphorus in end stage renal disease (ESRD) patients on haemodialysis was demonstrated in three Phase 2 studies with treatment duration ranging from 2 to 12 weeks and two Phase 3 studies with treatment duration of 8 weeks each. Four of the five studies were open-label dose-titration studies. One of the Phase 2 studies was a placebo-controlled study. The Phase 3 cross-over study, described below, had a control arm. About half the patients from these studies (N=192) were treated with RENAGEL capsules in a long-term open-label extension study of 44 weeks. In a cross-over study of sevelamer and calcium acetate, 84 ESRD patients on haemodialysis who were hyperphosphataemic (serum phosphorus > 1.94 mmol/L) following a 2-week phosphate binder washout period were randomised to receive either RENAGEL for 8 weeks followed by calcium acetate for 8 weeks or calcium acetate for 8 weeks followed by RENAGEL for 8 weeks. Treatment periods were separated by a 2-week phosphate binder washout period. Patients started on RENAGEL capsules or calcium acetate tablets 3 times per day with meals. Over each 8-week treatment period, at three separate time points the dose of either agent could be titrated up one capsule or tablet per meal (3 per day) to control serum phosphorus. RENAGEL and calcium acetate both significantly decreased mean serum phosphorus by about 0.65 mmol/L (Table 1). Table 1: Mean Serum Phosphorus at Baseline and Endpoint   RENAGEL® (n=81) Ca Acetate (n=83) Baseline at End of Washout 2.7 mmol/L 2.6 mmol/L Change from Baseline at Endpoint (95% Confidence Interval) - 0.65 mmol/L* (-0.81, -0.48) - 0.68 mmol/L* (-0.84, -0.55) *p < 0.0001, within treatment group comparison Figure 2 illustrates that the proportion of patients achieving a given level of serum phosphorus lowering is comparable between the two treatment groups. For example, about half the patients in each group had a decrease of at least 0.65 mmol/L at endpoint. Successful control of serum phosphorus in chronic kidney disease patients is multifactorial including reduction of dietary phosphate intake, removal of phosphate with dialysis and inhibition of intestinal phosphate absorption with phosphate binders. As seen in Figure 2, some of the patients in GTC-36-301 did not respond to sevelamer treatment. Not all patients achieve phosphorus control with sevelamer alone, especially at the doses administered in this study (average actual daily dose 4.3 g/day). Later studies which employed higher doses of sevelamer (i.e. GTC-49-301-average actual daily dose 6.5 g/day) had a better rate of phosphorus response. Figure 2: Cumulative percent of patients (Y-axis) attaining a phosphorus change from baseline at least as great as the value of the X-axis. A shift to the left of a curve indicates a better response. Average daily consumption at the end of treatment was 4.9 g sevelamer (range of 0.0 to 12.6 g) and 5.0 g of calcium acetate (range of 0.0 to 17.8 g). During calcium acetate treatment, 22% of patients developed serum calcium ≥ 2.75 mmol/L on at least one occasion versus 5% for sevelamer (p < 0.05). Thus the risk of developing hypercalcaemia is less with RENAGEL compared to calcium acetate. Mean LDL cholesterol and mean total cholesterol declined significantly on RENAGEL Capsules treatment (-24% and -15% respectively). Neither LDL nor total cholesterol changed on calcium acetate treatment. Triglycerides, high-density lipoprotein (HDL) cholesterol, and albumin did not change on either treatment. Similar reductions in serum phosphorus and LDL cholesterol were observed in an 8-week open-label, uncontrolled study of 172 end-stage renal disease patients on haemodialysis. In a parallel study of RENAGEL and calcium acetate or calcium carbonate, two hundred ESRD patients on haemodialysis who were hyperphosphataemic (serum phosphorus > 1.78 mmol/L) following a two-week phosphate binder washout period were randomised to receive RENAGEL 800 mg tablets (N=99) or calcium, either calcium acetate (N=54) or calcium carbonate (N=47). Seventy-seven percent of RENAGEL patients (N=76) and 80% of the calcium patients (N=81) completed the full 52 weeks of treatment with the major reason for dropout in the RENAGEL group was gastrointestinal adverse events. Calcium acetate and calcium carbonate produced comparable decreases in serum phosphorus. At week 52, using last-observation-carried-forward, RENAGEL and calcium both significantly decreased mean serum phosphorus (Table 2). Table 2: Mean Serum Phosphorus at Baseline and End of Treatment (52 weeks) Serum Phosphorus RENAGEL® (N=76) Calcium (N=81) Baseline 2.38 mmol/L 2.33 mmol/L Change from baseline at 52 weeks -0.72 mmol/L -0.64 mmol/L Mean serum phosphorus levels at 52 weeks 1.67 mmol/L 1.68 mmol/L Figure 3, a plot of the phosphorus change from baseline for the completers, illustrates the durability of response for patients who are able to remain on treatment. Figure 3: Mean Phosphorus Change from Baseline for Patients who Completed 52 Weeks of Treatment Average daily consumption at the end of the treatment was 6.5 g of sevelamer (range of 0.8 to 13 g) or approximately eight 800 mg tablets (range of 1 to 16 tablets), 4.6 g of calcium acetate (range of 0.7 to 9.5 g) and 3.9 g of calcium carbonate treatment, 34% of patients developed serum calcium corrected for albumin ≥ 2.75 mmol/L on at least one occasion versus 7% for RENAGEL (p<0.05). Thus the risk of developing hypercalcaemia is less with RENAGEL compared to calcium salts. Mean LDL cholesterol and mean total cholesterol declined significantly (p<0.05) on RENAGEL treatment (-32% and -20%, respectively) compared to calcium (+0.2% and -2%, respectively) triglycerides, HDL cholesterol, and albumin did not change. INDICATIONS RENAGEL is indicated for the management of hyperphosphataemia in adult patients with stage 4 and 5 chronic kidney disease. CONTRAINDICATIONS RENAGEL is contraindicated in patients with hypophosphataemia or bowel obstruction. RENAGEL is also contraindicated in patients known to be hypersensitive to sevelamer hydrochloride or any of the other components of the tablet. PRECAUTIONS General The safety and efficacy of RENAGEL in patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders, severe constipation or major GI tract surgery have not been established. Consequently, caution should be exercised when RENAGEL is used in patients with these GI disorders. Patients with renal insufficiency may develop hypocalcaemia or hypercalcaemia. RENAGEL does not contain calcium. Serum calcium levels should be monitored as is done in routine follow-up of a dialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia. Patients with chronic kidney disease are predisposed to metabolic acidosis. RENAGEL does not contain alkali supplementation: serum bicarbonate and chloride levels should be monitored. In non clinical studies in rats and dogs, sevelamer hydrochloride reduced vitamin D, E and folic acid levels at doses of 0.6 - 10 g/kg/day which are 6 -100 times the recommended average clinical dose based on a mg/kg basis. In clinical trials, there was no evidence of reduction in serum levels of vitamins with the exception of a one year clinical trial in which RENAGEL treatment was associated with reduction of 25-hydroxyvitamin D (normal range 10 to 55 µg/mL) from 39± 22 µg/mL to 34± 22 µg/mL (p<0.01). Most patients in RENAGEL clinical trials received vitamin supplements, which is typical of patients on haemodialysis. Indirect evidence of a reduction in vitamin K levels (an increase in haemorrhage corrected by vitamin K supplementation) was also seen in animals. Carcinogenicity/Mutagenicity Sevelamer hydrochloride was administered in the diet to rats and mice for two years. In mice and female rats, there was no increase in the incidence of tumours. In male rats, there was an increased incidence of transitional cell papillomas and transitional cell carcinomas in the urinary bladder at a dose of 3 g/kg/day, which is 10 times the maximum daily human dose (mg/kg basis) for a 50 kg person examined in clinical trials. These findings were considered likely to be secondary to increased serum and urinary calcium levels and inflammatory responses in the urinary bladder and their relevance to humans is unknown. In an in vitro mammalian cytogenetics test with metabolic activation, sevelamer hydrochloride caused a statistically significant increase in the number of structural chromosome aberrations. Sevelamer hydrochloride was not mutagenic in the Ames bacterial mutation assay. Based on the available evidence, sevelamer hydrochloride is considered unlikely to be genotoxic in vivo following oral administration. Impairment of Fertility Sevelamer hydrochloride administered orally to male and female rats prior to and throughout mating, at doses up to 4.5 g/kg/day (15 times the maximum tested human dose on a mg/kg basis of a 50 kg person) did not alter mating or fertility. Use in Pregnancy - Pregnancy Category B3 There was no evidence of teratogenicity in rabbits or rats following oral administration of sevelamer hydrochloride during the period of organogenesis at respective doses 1.5 and 4.5 g/kg/day (5 and 15 times respectively on a mg/kg basis for a 50 kg human). In rats receiving doses of 1.5 and 4.5 g/kg/day during organogenesis, there was reduced or irregular ossification of foetal bonds at exposures of 5 and 15 times the maximum tested human dose. In rabbits receiving 1 g/kg/day during organogenesis, there was an increase in early resorptions leading to a reduction in the number of live foetuses per litter at an exposure 3.3 times the maximum recommended human dose. Oral administration of sevelamer hydrochloride to female rats throughout gestation and lactation at doses of 0.1 - 1 g/kg/day (exposure 0.3 - 3.3 times the maximum recommended human dose) did not affect the birth or growth of their offspring or their postnatal development. The safety of sevelamer hydrochloride in human pregnancy has not been established and, because animal reproduction studies are not always predictive of human responses, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Use in Lactation Oral administration of sevelamer hydrochloride to female rats throughout gestation and lactation did not have any adverse effects on offspring (see Use in Pregnancy). No adequate and controlled studies have been conducted using sevelamer in nursing mothers. RENAGEL tablets should be used during breastfeeding only if the potential benefit justifies the potential risks. Use in Children The safety and effectiveness of RENAGEL in paediatric patients have not been established. Instructions to Patients The contents of RENAGEL expand in water thus tablets should be swallowed intact and should not be crushed, chewed or broken into pieces prior to administration. Interactions RENAGEL was studied in human drug-drug interaction studies with digoxin, warfarin, enalapril, metoprolol, iron and ciprofloxacin. In interaction studies in healthy volunteers, RENAGEL had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol. However, the bioavailability of ciprofloxacin was decreased by approximately 50% when co-administered with RENAGEL in a single dose study. Consequently, RENAGEL should not be taken simultaneously with ciprofloxacin. 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. 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. Special precautions should be taken when prescribing RENAGEL to patients also taking these medications. RENAGEL may affect the bioavailability of other medicinal products. When administering a medicinal product where a reduction in the bioavailability of that product could have a clinically significant effect on its 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. ADVERSE EFFECTS In a placebo-controlled study with a treatment duration of two weeks, the adverse events reported for RENAGEL capsules (N=24) were similar to those reported for placebo (N=12). In a cross-over study with the treatment durations of eight weeks, the adverse events reported for RENAGEL capsules (N=82) were similar to those reported for calcium acetate (N=82) and included headache, infection, pain, hypotension, hypertension, thrombosis, diarrhoea, dyspepsia, vomiting and cough increased. In a parallel design study with treatment duration of 52 weeks, adverse events reported for RENAGEL Tablets (N=99) were similar to those reported for calcium (calcium acetate and calcium carbonate) (N=101), except for a significantly higher incidence of dyspepsia in the RENAGEL group. Furthermore, gastrointestinal adverse events were the major reason for withdrawals in the RENAGEL group (Table 3). In the long term, open label extension trial, adverse events possibly related to RENAGEL capsules and which were not dose-related included nausea (7%), constipation (2%), diarrhoea (4%), flatulence (4%) and dyspepsia (5%). Table 3: Treatment-Emergent Adverse Events ≥ 10% from a Parallel Design Trial of RENAGEL® tablets versus Calcium Acetate for 52 Weeks of Treatment Adverse Event RENAGEL® (N=99) Calcium (N=101)   Patients (%) Patients (%) Gastrointestinal Disorders     Vomiting 22.2 21.8 Nausea 20.2 19.8 Diarrhoea 19.2 22.8 Dyspepsia 16.2 6.9 Constipation 8.1 11.9 Infections and Infestations     Nasopharyngitis 14.1 7.9 Bronchitis 11.1 12.9 Upper Respiratory Tract Infection 5.1 10.9 Musculoskeletal Connective Tissue and Bone Disorders     Pain in Limb 13.1 14.9 Arthralgia 12.1 17.8 Back Pain 4.0 17.8 Skin Disorders     Pruritus 13.1 9.9 Respiratory, Thoracic and Mediastinal Disorders     Dyspnoea 10.1 16.8 Cough 7.1 12.9 Vascular Disorders     Hypertension 10.1 5.9 Nervous System Disorders     Headache 9.1 15.8 General Disorders and Site Administration Disorders     Mechanical Complication of Implant 6.1 10.9 Pyrexia 5.1 10.9 During post-marketing experience with RENAGEL, the following have been reported, although no direct relationship to RENAGEL could be established: pruritis, rash and abdominal pain. In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment with RENAGEL. Constipation might be a preceding symptom indicating the development of intestinal obstruction. Hence, patients with severe constipation should be monitored carefully while being treatment with RENAGEL. DOSAGE AND ADMINISTRATION The recommended starting dose for patients not taking a phosphate binder is 800 to 1600 mg (Table 4), which can be administered as one to two RENAGEL tablets with each meal based on serum phosphorus level. Table 4: Starting Dose for Patients not Taking a Phosphate Binder Serum Phosphorus RENAGEL® > 1.78 and < 2.42 mmol/L 1 tablet, three times daily with meals ≥ 2.42 and <2.91 mmol/L 2 tablets, three times daily with meals ≥ 2.91 mmol/L 2 tablets, three times daily with meals When patients are converting from a calcium based phosphate binder, RENAGEL should be given in equivalent doses on a (mg to mg) weight basis compared to the patient's previous calcium based phosphate binder (Table 5). Serum phosphorus levels should be closely monitored and the dose of RENAGEL adjusted accordingly with the goal of lowering serum phosphorus. Serum phosphorus should be tested every 2 to 3 weeks until a stable serum phosphorus level is reached, and on a regular basis thereafter. Table 5: Starting Dose for Patients Switching from Calcium Acetate to RENAGEL® Calcium Acetate 667 mg (tablets per meal) RENAGEL® (tablets per meal) 1 tablet 1 tablet 2 tablets 2 tablets 3 tablets 3 tablets The dosage should be gradually adjusted based on the serum phosphorus concentration with a goal of lowering serum phosphorus. The dose may be increased or decreased by one tablet per meal at two week intervals as necessary (Table 6). The average dose in a one year phase 3 trial designed to lower serum phosphorus to 1.62 mmol/L or less was approximately three RENAGEL tablets per meal. The average actual daily dose used in the chronic phase of a one year clinical study was 7 grams of sevelamer hydrochloride. Table 6: Dose Titration Guideline 800mg tablets Serum Phosphorus RENAGEL® Dose > 1.78 mmol/L Increase 1 tablet per meal at 2 week intervals 1.13 - 1.78 mmol/L Maintain current dose < 1.13 mmol/L Decrease 1 tablet per meal Patients should be advised not to chew the tablets as sevelamer hydrochloride swells on contact with moisture. Patients should swallow the tablets whole with water. OVERDOSAGE RENAGEL has been given to normal healthy volunteers in doses of up to 14 grams per day for 8 days with no adverse effects. There are no reported overdoses of RENAGEL in patients. Since RENAGEL is not absorbed, the risk of systemic toxicity is low. Contact the Australian Poisons Information Centre (telephone 13 11 26), or the New Zealand National Poisons Information Centre (telephone 0800 POISON or 0800 764 766) for advice on management. PRESENTATION AND STORAGE CONDITIONS RENAGEL tablets are oval film-coated tablets imprinted with "RENAGEL 800" on the crown, single side. RENAGEL tablets contain 800 mg of the active ingredient sevelamer hydrochloride on an anhydrous basis. The tablets are packaged in white high-density polyethylene bottles, with a child resistant polypropylene cap and an induction seal. RENAGEL tablets are available in a pack size of 180. Store below 25°C. Do not refrigerate. Protect from moisture. Keep the container tightly closed. NAME AND ADDRESS OF THE SPONSOR Australia Genzyme Australasia Pty Ltd. Level 1, Building C 12-24 Talavera Road North Ryde NSW 2113 AUSTRALIA