原发性甲状旁腺机能亢进症(甲旁亢)是由于甲状旁腺腺瘤(单个腺瘤占绝大多数，约75%)、增生或腺癌(罕见)导致甲状旁腺素(PTH)分泌过多，引起骨、肾、消化、神经系统等病变及钙磷代谢紊乱疾病。 本病好发于女性，男女之比约1：2￣4，妇女绝经期发病率最高，在一组选择性病例调查中，〉40岁者甲旁亢的发生率高达1/1000￣1/200。本病一经确诊，即行手术切除可获治愈 研究人员昨天说，阿目金生技公司的Sensipar (cinacalcet)是原发性甲状旁腺功能亢进症的一种有效治疗，它提供了手术之外的另一种选择。 据在美国骨和矿物质研究学会西雅图会议上提交的一项多中心试验资料说，在一项对22名原发性甲状旁腺功能亢进症病人的试验中，80%使用了Sensipar的病人血浆钙水平正常化，18人治疗3年仍保持了血浆钙的降低。 阿目金公司称，目前本病在美国有50万病人，唯一确定有效的治疗是手术切除一个或以上甲状旁腺。 Sensipar，是一种拟钙剂，3月ＦＤＡ批准它来治疗透析的慢性肾病患者的继发性甲状旁腺功能亢进症，及降低甲状旁腺癌症病人血液中增高的血钙水平。 世界最大的生物技术公司安进公司宣布，欧洲人用药品委员会(CHMP)已经批准Mimpara (cinacalcet HCl)在欧盟上市，用于慢性肾衰（CKD）透析患者继发性甲状旁腺功能亢进（HPT）以及甲状旁腺癌患者高钙血症的治疗。该药以Sensipar为商品名在美国经销，是在2004年3月按照优先审批程序获得美国FDA批准的。Mimpara是一种新型的拟钙剂，可通过增强钙敏感受体对细胞外钙的敏感性而直接降低甲状旁腺素水平。 Cinacalcet是第一个获FDA批准的calcimimetics（拟钙剂）类化合物。其获准用于慢性肾功衰竭透析患者的继发性甲状旁腺功能亢进。它可以提高甲状旁腺素（PTH）的水平，继发性甲状旁腺功能亢进的特点是钙磷代谢异常、骨痛、骨折、增加心血管疾病的死亡风险。Cinacalcet治疗可同时降低PTH的血清水平以及钙磷乘积，钙磷乘积是血中钙磷水平的测量标准，当其升高时，体内各部分出现钙沉积，危害身体。 Cinacalcet还获准用于副甲状腺癌患者的高血钙症，副甲状腺癌是一种罕见的癌症，可引起严重的高钙血症。血清钙升高可引起精神错乱、嗜眠、脱水、恶心、呕吐、便秘、肾功能损害。 在一个由1000多位接受透析治疗的慢性肾功能患者参与的为期6个月的Cinacalcet临床试验中，最常见的不良反应是恶心、呕吐，发生率分别是31%和27%，而接受安慰剂的恶心、呕吐的发生率分别是19%和15%。大多数的慢性肾功能患者还出现了低钙血症。因此在标签中有监测患者血钙水平的提示。 英文药名: Sensipar (Cinacalcet Tablets) 中文药名: 盐酸西那卡塞片 品牌药生产厂家: Amgen Inc 药品介绍 商品名：Ｓｅｎｓｉｐａｒ（安进公司）盐酸西那卡塞（Ｃｉｎａｃａｌｃｅｔ Ｈｙｄｒｏｃｈｌｏｒｉｄｅ）是一种拟钙剂，当它与维生素Ｄ类似物和磷酸盐结合剂合用时，可降低体内甲状旁腺素（ＰＴＨ）和血清钙水平。该药于２００４年３月８日获得美国食品药品管理局（ＦＤＡ）批准。 生物技术公司-安进(Amgen Inc)2004年7月30日宣布，该公司生产的新药Mimpara获得欧盟人用药品委员会推荐。该药于今年3月获FDA批准，通用名为cinacalcet HCI,在美国以商品名Sensipar上市。 Cinacalcet是第一种被FDA批准的此类药物。PTH水平升高是甲状旁腺功能亢进的标志，改变钙磷代谢，使骨质疏松，并且是冠心病的诱发因素。Cinacalcet可以降低血清PTH水平，从而调节钙磷代谢。Cinacalcet还可以治疗甲状旁腺癌引起的高钙血症。血液中钙含量过多可以引起明显的精神混乱、嗜睡、脱水、恶心呕吐、便秘和肾损伤。 CinacalcetHCl是新分子实体(NME)。Sensipar是一种具有独特作用机理的口服化合物。它调节甲状旁腺钙受体的行为，通过增强受体对血流中钙水平的敏感性，它降低甲状旁腺激素、钙、磷和钙-磷产品的水平。目前，还没有具有这些特性的治疗药出现。它获准的适应症为，用于治疗慢性肾病(CKD)行透析病人的继发性甲状旁腺功能亢进(继发性HPT)和用于治疗甲状旁腺癌患者的钙水平升高(高钙血)。对于两者Sensipar都是一个明显的医疗进步。这是Amgen公司(它是NPS制药公司这个产品的许可权受让人)的第一个小分子治疗药，同时也是自1990年代初发现calcimimetic化合物以来第一个这类使肾和甲状旁腺病患者得益的药物。 经过6个月1000多个接受血透治疗的慢性肾衰患者临床试验证明，本药最主要的副作用为恶心呕吐。使用本药的患者恶心发生率31％，呕吐发生率27％，而使用安慰剂的患者其发生率分别为19%和15%。使用本药对肾衰患者的高钙血症也有明显作用。 药理及药代动力学 该药可与甲状旁腺中的钙敏感受体结合，减少甲状旁腺素的分泌，进而导致血清钙及磷酸钙产物水平的降低。通常而言，原发性甲状旁腺功能亢进患者会在服用该药第二剂后２小时内观察到最初的治疗反应；在治疗开始后４～６周内观察到持续的治疗反应该药达峰时间为２～６小时。该药与高脂饮食同服时，可导致血药浓度和药时曲线下面积（ＡＵＣ）升高。该药蛋白结合率为９３％～９７％，分布容积达１０００升。细胞色素Ｐ４５０ ３Ａ４、２Ｄ６和１Ａ２均与该药代谢有关。代谢产物主要通过尿液（８０％）和粪便（１５％）排泄，消除半衰期为４０小时。 适应症 该药主要用于治疗肾病透析患者的继发性甲状旁腺机能亢进，或者甲状旁腺癌所致的高钙血症。 用法用量 该药应整片吞服，初始剂量为３０ｍｇ／天，进食时服用。随后根据患者反应情况，每２～４周调整一次剂量（按６０ｍｇ／天、９０ｍｇ／天、１２０ｍｇ／天和１８０ｍｇ／天顺序依次递增），直至患者ＰＴＨ水平达到美国肾脏基金会临床指南推荐的标准（１５０～３００ｐｇ／ｍｌ）。该药可单独应用或与维生素Ｄ醇和磷酸盐结合剂合用。 任何疑问，请遵医嘱！ 不良反应 临床试验中该药最常见的不良事件为恶心和呕吐。其他发生率大于５％的不良事件还包括腹泻、肌痛、高血压、无力、食欲减退、非心脏性胸痛和通路感染（ａｃｃｅｓｓ 此外，西那卡塞治疗组和安慰剂对照组的严重感染发生率基本相当。 注意事项 该药可降低血清钙水平，因而可能引起低钙血症。患者应注意观察是否有感觉异常、肌痛、痉挛、手足抽搐和惊厥的发生。 药物相互作用 该药是细胞色素Ｐ４５０ ２Ｄ６（ＣＹＰ２Ｄ６）同功酶的抑制剂，因此，当该药与同样通过ＣＹＰ２Ｄ６代谢，且治疗指数较小的药物（如氟卡胺、长春碱、硫利达嗪和大多数三环类抗抑郁药）合用时，后者可能需要调整给药剂量。开始应用或停用ＣＹＰ３Ａ４强抑制剂（如酮康唑、红霉素或伊曲康唑）时，均有可能导致同时应用的该药的血药浓度发生较大幅度改变，因而需相应调整该药剂量。   DESCRIPTION Sensipar™ (cinacalcet hydrochloride) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Its empirical formula is C 22 H 22 F 3 N·HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity. Cinacalcet HCl is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water. Sensipar™ tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet HCl as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively). Cinacalcet HCl is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula: Inactive Ingredients:    Sensipar™ tablets are comprised of the active ingredient, and the following inactive ingredients: pre-gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide, and magnesium stearate. Tablets are coated with color (Opadry® II green) and clear film-coat (Opadry® clear), carnauba wax, and Opacode® black ink. CLINICAL PHARMACOLOGY Mechanism of Action Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis. The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Sensipar™ directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. Pharmacokinetics Absorption and Distribution:    After oral administration of cinacalcet, maximum plasma concentration (C max ) is achieved in approximately 2 to 6 hours. A food-effect study in healthy volunteers indicated that the C max and area under the curve (AUC (0-inf) ) were increased 82% and 68%, respectively, when cinacalcet was administered with a high-fat meal compared to fasting. C max and AUC (0-inf) of cinacalcet were increased 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared to fasting. After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days. The mean accumulation ratio is approximately 2 with once-daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice-daily oral administration. The AUC and C max of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once-daily dosing of 30 to 180 mg. The volume of distribution is high (approximately 1000 L), indicating extensive distribution. Cinacalcet is approximately 93 to 97% bound to plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL. Metabolism and Excretion:    Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via (beta)-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are further conjugated with glucuronic acid. The plasma concentrations of the major circulating metabolites including the cinnamic acid derivatives and glucuronidated dihydrodiols markedly exceed parent drug concentrations. The hydrocinnamic acid metabolite was shown to be inactive at concentrations up to 10 µM in a cell-based assay measuring calcium-receptor activation. The glucuronide conjugates formed after cinacalcet oxidation were shown to have a potency approximately 0.003 times that of cinacalcet in a cell-based assay measuring a calcimimetic response. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces. Special Populations Hepatic Insufficiency:    The disposition of a 50 mg cinacalcet single dose was compared in patients with hepatic impairment and subjects with normal hepatic function. Cinacalcet exposure, AUC (0-inf) , was comparable between healthy volunteers and patients with mild hepatic impairment. However, in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method), cinacalcet exposures as defined by the AUC (0-inf) were 2.4 and 4.2 times higher, respectively, than that in normals. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function. See PRECAUTIONS and DOSAGE AND ADMINISTRATION . Renal Insufficiency:    The pharmacokinetic profile of a 75 mg Sensipar™ single dose in patients with mild, moderate, and severe renal insufficiency, and those on hemodialysis or peritoneal dialysis is comparable to that in healthy volunteers. Geriatric Patients:    The pharmacokinetic profile of Sensipar™ in geriatric patients (age >/= 65, n = 12) is similar to that for patients who are < 65 years of age (n = 268). Pediatric Patients:    The pharmacokinetics of Sensipar™ have not been studied in patients < 18 years of age. Drug Interactions An in vitro study indicates that cinacalcet is a strong inhibitor of CYP2D6, but not of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. Ketoconazole:   Cinacalcet AUC (0-inf) and C max increased 2.3 and 2.2 times, respectively, when a single 90 mg cinacalcet dose on Day 5 was administered to subjects treated with 200 mg ketoconazole twice daily for 7 days compared to 90 mg cinacalcet given alone (see DOSAGE AND ADMINISTRATION ). Calcium Carbonate:   No significant pharmacokinetic interaction was observed when 1500 mg calcium carbonate was coadministered with 100 mg cinacalcet. Pantoprazole:   No significant pharmacokinetic interaction was observed when cinacalcet 90 mg was administered to subjects treated with 80 mg pantoprazole daily for 3 days. Sevelamer HCl:   No significant pharmacokinetic interaction was observed when 2400 mg sevelamer HCl was coadministered with 90 mg cinacalcet tablet (subjects subsequently received 2400 mg sevelamer HCl two more times on Day 1 and three more times on Day 2). Amitriptyline:   Concurrent administration of 25 mg or 100 mg cinacalcet with 50 mg amitriptyline increased amitriptyline exposure and nortriptyline (active metabolite) exposure by approximately 20% in CYP2D6 extensive metabolizers. Warfarin:   R-and S-warfarin pharmacokinetics and warfarin pharmacodynamics were not affected in subjects treated with warfarin 25 mg who received cinacalcet 30 mg twice daily. The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the absence of auto-induction upon multiple dosing in patients indicates that cinacalcet is not an inducer of CYP2C9 in humans. Pharmacodynamics Reduction in intact PTH (iPTH) levels correlated with cinacalcet concentrations in CKD patients. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the C max of cinacalcet. After steady state is reached, serum calcium concentrations remain constant over the dosing interval in CKD patients. CLINICAL STUDIES Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in CKD patients on dialysis. A total of 665 patients were randomized to Sensipar™ and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% Caucasian. The average baseline iPTH level by the Nichols intact immunoradiometric assay (IRMA) was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P ion product was 61 mg 2 /dL 2 . The average duration of dialysis prior to study enrollment was 67 months. Ninety-six percent of patients were on hemodialysis and 4% peritoneal dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93% were receiving phosphate binders. Sensipar™ (or placebo) was initiated at a dose of 30 mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of </= 250 pg/mL. The dose was not increased if a patient had any of the following: iPTH </= 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders could be increased. If these measures were insufficient, the vitamin D dose could be increased. Approximately 70% of the Sensipar™ patients and 80% of the placebo patients completed the 6-month studies. In the primary efficacy analysis, 40% of Sensipar™ patients and 5% of placebo patients achieved an iPTH </= 250 pg/mL (p<0.001) (Table 1, Figure 1). Secondary efficacy parameters also improved in patients treated with Sensipar™. These studies showed that Sensipar™ reduced PTH while lowering Ca x P, calcium and phosphorus levels (Table 1, Figure 2). The median dose of Sensipar™ at the completion of the studies was 90 mg. Patients with milder disease typically required lower doses. Table 1. Effects of Sensipar™ on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies (Patients on Dialysis)    Study 1 Study 2 Study 3 Placebo (N = 205) Sensipar™ (N = 205) Placebo (N = 165) Sensipar™ (N = 166) Placebo (N = 101) Sensipar™ (N = 294) iPTH                 Baseline (pg/mL: Median 535 537 556 547 670 703                               Median (SD) 651 (398) 636 (341) 630 (317) 652 (372) 832 (486) 848 (685)    Evaluation Phase (pg/mL) 563 275 592 238 737 339    Median Percent Change +3.8 -48.3 +8.4 -54.1 +2.3 -48.2    Patients Achieving Primary Endpoint      (iPTH) </= 250 pg/mL) (%) a 4% 41% ** 7% 46% ** 6% 35% **    Patients Achieving >/= 30% Reduction in      iPTH (%) a 11% 61% 12% 68% 10% 59%    Patients Achieving iPTH </= 250 pg/mL and    Ca x P < 55 mg 2 /dL 2 (%) 1% 32% 5% 35% 5% 28% Ca x P                Baseline (mg 2 /dL 2 ) 62 61 61 61 61 59    Evaluation Phase (mg 2 /dL 2 ) 59 52 59 47 57 48    Median Percent Change -2.0 -14.9 -3.1 -19.7 -4.8 -15.7 Calcium                Baseline (mg/dL) 9.8 9.8 9.9 10.0 9.9 9.8    Evaluation Phase (mg/dL) 9.9 9.1 9.9 9.1 10.0 9.1     Median Percent Change +0.5 -5.5 +0.1 -7.4 +0.3 -6.0 Phosphorus                Baseline (mg/dL) 6.3 6.1 6.1 6.0 6.1 6.0    Evaluation Phase (mg/dL) 6.0 5.6 5.9 5.1 5.6 5.3    Median Percent Change -1.0 -9.0 -2.4 -12.4 -5.6 -8.6 ** p < 0.001 compared to placebo; p-values presented for primary endpoint only a iPTH value based on averaging over the evaluation phase (defined as weeks 13 to 26 in studies 1 and 2 and weeks 17 to 26 in study 3) Values shown are medians unless indicated otherwise Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment. Sensipar™ decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH >/= 300 to </= 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA. In CKD patients with secondary HPT not on dialysis, the long-term safety and efficacy of Sensipar™ have not been established. Exploratory investigation indicates that CKD patients not on dialysis have an increased risk for hypocalcemia compared to CKD patients on dialysis, which may be due to lower baseline calcium levels. In a small, short-term study, in which the median dose of cinacalcet was 30 mg at the completion of the study, 74% of cinacalcet-treated patients experienced at least one serum calcium value < 8.4 mg/dL (see PRECAUTIONS Hypocalcemia ). Parathyroid Carcinoma Ten patients with parathyroid carcinoma were enrolled in an open-label study. The study consisted of 2 phases, a dose-titration phase and a maintenance phase. The range of exposure was 2 to 16 weeks in the titration phase (n = 10) and 16 to 48 weeks (n = 3) for the maintenance phase. Baseline mean (SD) serum calcium was 14.7 (1.8) mg/dL. The range of change from baseline to last measurement was -7.5 to 2.7 mg/dL during the titration phase and -7.4 to 0.9 mg/dL during the maintenance phase (Figure 3). No patients maintained a serum calcium level within the normal range. The doses ranged from 70 mg twice daily to 90 mg four times daily for patients in the maintenance phase. INDICATIONS AND USAGE Sensipar™ is indicated for the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease on dialysis. Sensipar™ is indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma. CONTRAINDICATIONS Sensipar™ is contraindicated in patients with hypersensitivity to any component(s) of this product. WARNINGS Seizures In three clinical studies of CKD patients on dialysis, 5% of the patients in both the Sensipar™ and placebo groups reported a history of seizure disorder at baseline. During the trials, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (9/656) of Sensipar™-treated patients and 0.4% (2/470) of placebo-treated patients. Five of the nine Sensipar™-treated patients had a history of a seizure disorder and two were receiving anti-seizure medication at the time of their seizure. Both placebo-treated patients had a history of seizure disorder and were receiving anti-seizure medication at the time of their seizure. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Therefore, serum calcium levels should be closely monitored in patients receiving Sensipar™, particularly in patients with a history of a seizure disorder (see PRECAUTIONS , Hypocalcemia ). PRECAUTIONS General Hypocalcemia Sensipar™ lowers serum calcium, and therefore patients should be carefully monitored for the occurrence of hypocalcemia. Potential manifestations of hypocalcemia include paresthesias, myalgias, cramping, tetany, and convulsions. Sensipar™ treatment should not be initiated if serum calcium is less than the lower limit of the normal range (8.4 mg/dL). Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar™. Once the maintenance dose has been established, serum calcium should be measured approximately monthly (see DOSAGE AND ADMINISTRATION ). If serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold administration of Sensipar™ until serum calcium levels reach 8.0 mg/dL, and/or symptoms of hypocalcemia have resolved. Treatment should be re-initiated using the next lowest dose of Sensipar™ (see DOSAGE AND ADMINISTRATION ). In the 26-week studies of patients with CKD on dialysis, 66% of patients receiving Sensipar™ compared with 25% of patients receiving placebo developed at least one serum calcium value < 8.4 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia. In CKD patients with secondary HPT not on dialysis, the long-term safety and efficacy of Sensipar™ have not been established. Exploratory investigation indicates that CKD patients not on dialysis have an increased risk for hypocalcemia compared to CKD patients on dialysis, which may be due to lower baseline calcium levels. In a small, short-term study, in which the median dose of cinacalcet was 30 mg at the completion of the study, 74% of cinacalcet-treated patients experienced at least one serum calcium value < 8.4 mg/dL. Adynamic Bone Disease Adynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL when assessed using the standard Nichols IRMA. One clinical study evaluated bone histomorphometry in patients treated with Sensipar™ for one year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar™. Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In the three 6-month, phase 3 studies conducted in CKD patients on dialysis, 11% of patients treated with Sensipar™ had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below the NKF-K/DOQI recommended target range (150-300 pg/mL) 1 in patients treated with Sensipar™, the dose of Sensipar™ and/or vitamin D sterols should be reduced or therapy discontinued. Hepatic Insufficiency Cinacalcet exposure as assessed by AUC (0-inf) in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method) were 2.4 and 4.2 times higher, respectively, than that in normals. Patients with moderate and severe hepatic impairment should be monitored throughout treatment with Sensipar™ (see CLINICAL PHARMACOLOGY , Pharmacokinetics and DOSAGE AND ADMINISTRATION ). Information for Patients It is recommended that Sensipar™ be taken with food or shortly after a meal. Tablets should be taken whole and should not be divided. Laboratory Tests Patients with CKD on Dialysis with Secondary Hyperparathyroidism Serum calcium and serum phosphorus should be measured within 1 week and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar™. Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and PTH every 1 to 3 months (see DOSAGE AND ADMINISTRATION ). All iPTH measurements during the Sensipar™ trials were obtained using the Nichols IRMA. In patients with end-stage renal disease, testosterone levels are often below the normal range. In a placebo-controlled trial in patients with CKD on dialysis, there were reductions in total and free testosterone in male patients following six months of treatment with Sensipar™. Levels of total testosterone decreased by a median of 15.8% in the Sensipar™-treated patients and by 0.6% in the placebo-treated patients. Levels of free testosterone decreased by a median of 31.3% in the Sensipar™-treated patients and by 16.3% in the placebo-treated patients. The clinical significance of these reductions in serum testosterone is unknown. Patients with Parathyroid Carcinoma Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar™. Once maintenance dose levels have been established, serum calcium should be measured every 2 months (see DOSAGE AND ADMINISTRATION ). Drug Interactions and/or Drug/Laboratory Test Interactions See CLINICAL PHARMACOLOGY , Pharmacokinetics and Drug Interactions . Effect of Sensipar™ on other drugs: Drugs metabolized by cytochrome P450 2D6 (CYP2D6): Sensipar™ is a strong in vitro inhibitor of CYP2D6. Therefore, dose adjustments of concomitant medications that are predominantly metabolized by CYP2D6 and have a narrow therapeutic index (e.g., flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required. Amitriptyline:   Concurrent administration of 25 mg or 100 mg cinacalcet with 50 mg amitriptyline increased amitriptyline exposure and nortriptyline (active metabolite) exposure by approximately 20% in CYP2D6 extensive metabolizers. Effect of other drugs on Sensipar™: Sensipar™ is metabolized by multiple cytochrome P450 enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. Ketoconazole:   Sensipar™ is metabolized in part by CYP3A4. Co-administration of ketoconazole, a strong inhibitor of CYP3A4, increased cinacalcet exposure following a single 90 mg dose of Sensipar™ by 2.3 fold. Dose adjustment of Sensipar™ may be required and PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, erythromycin, itraconazole; see DOSAGE AND ADMINISTRATION ). Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenicity:    Standard lifetime dietary carcinogenicity bioassays were conducted in mice and rats. Mice were given dietary doses of 15, 50, 125 mg/kg/day in males and 30, 70, 200 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Rats were given dietary doses of 5, 15, 35 mg/kg/day in males and 5, 20, 35 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). No increased incidence of tumors was observed following treatment with cinacalcet. Mutagenicity:    Cinacalcet was not genotoxic in the Ames bacterial mutagenicity assay or in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO cell chromosomal aberration assay, with and without metabolic activation or in the in vivo mouse micronucleus assay. Impairment of fertility:    Female rats were given oral gavage doses of 5, 25, 75 mg/kg/day beginning 2 weeks before mating and continuing through gestation day 7. Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2 weeks post-mating. No effects were observed in male or female fertility at 5 and 25 mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects (slight decreases in body weight and food consumption) in males and females. Pregnancy Category C In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day during gestation no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain). In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day during gestation no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day. In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day during gestation through lactation no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day (exposures 2-3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body-weight gain. Sensipar™ has been shown to cross the placental barrier in rabbits. There are no adequate and well-controlled studies in pregnant women. Sensipar™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Lactating Women Studies in rats have shown that Sensipar™ is excreted in the milk with a high milk-to-plasma ratio. It is not known whether this drug is excreted in human milk. Considering these data in rats and because many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in infants from Sensipar™, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the lactating woman. Pediatric Use The safety and efficacy of Sensipar™ in pediatric patients have not been established. Geriatric Use Of the 1136 patients enrolled in the Sensipar™ phase 3 clinical program, 26% were >/= 65 years old, and 9% were >/= 75 years old. No differences in the safety and efficacy of Sensipar™ were observed in patients greater or less than 65 years of age (see DOSAGE AND ADMINISTRATION , Geriatric Patients ). ADVERSE EVENTS Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis In 3 double-blind placebo-controlled clinical trials, 1126 CKD patients on dialysis received study drug (656 Sensipar™, 470 placebo) for up to 6 months. The most frequently reported adverse events (incidence of at least 5% in the Sensipar™ group and greater than placebo) are provided in Table 2. The most frequently reported events in the Sensipar™ group were nausea and vomiting. Table 2. Adverse Event Incidence (>/= 5%) in Patients on Dialysis Event * : Placebo (n = 470) (%) Sensipar™ (n = 656) (%) Nausea 19 31 Vomiting 15 27 Diarrhea 20 21 Myalgia 14 15 Dizziness   8 10 Hypertension   5   7 Asthenia   4   7 Anorexia   4   6 Pain Chest, Non-Cardiac   4   6 Access Infection   4   5 The incidence of serious adverse events (29% vs. 31%) was similar in the Sensipar™ and placebo groups, respectively. 12-Month Experience with Sensipar™:    Two hundred and sixty-six patients from 2 phase 3 studies continued to receive Sensipar™ or placebo treatment in a 6-month double-blind extension study (12-month total treatment duration). The incidence and nature of adverse events in this study were similar in the two treatment groups, and comparable to those observed in the phase 3 studies. Parathyroid Carcinoma The most frequent adverse events in this patient group were nausea and vomiting. Laboratory values:    Serum calcium levels should be closely monitored in patients receiving Sensipar™ (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ). OVERDOSAGE Doses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of Sensipar™ may lead to hypocalcemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels (see PRECAUTIONS ). Since Sensipar™ is highly protein bound, hemodialysis is not an effective treatment for overdosage of Sensipar™. DOSAGE AND ADMINISTRATION Sensipar™ tablets should be taken whole and should not be divided. Sensipar™ should be taken with food or shortly after a meal. Dosage must be individualized. Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis The recommended starting oral dose of Sensipar™ is 30 mg once daily. Serum calcium and serum phosphorus should be measured within 1 week and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar™. Sensipar™ should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 60, 90, 120, and 180 mg once daily to target iPTH consistent with the NKF-K/DOQI recommendation for CKD patients on dialysis of 150-300 pg/mL. Sensipar™ can be used alone or in combination with vitamin D sterols and/or phosphate binders. During dose titration, serum calcium levels should be monitored frequently and if levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with Sensipar™ (see PRECAUTIONS ). Parathyroid Carcinoma The recommended starting oral dose of Sensipar™ is 30 mg twice daily. The dosage of Sensipar™ should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to normalize serum calcium levels. Special Populations Geriatric patients:    Age does not alter the pharmacokinetics of Sensipar™; no dosage adjustment is required for geriatric patients. Patients with renal impairment:    Renal impairment does not alter the pharmacokinetics of Sensipar™; no dosage adjustment is necessary for renal impairment. Patients with hepatic impairment:    Cinacalcet exposures, as assessed by AUC (0-inf) , in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method) were 2.4 and 4.2 times higher, respectively, than in normals. In patients with moderate and severe hepatic impairment, PTH and serum calcium concentrations should be closely monitored throughout treatment with Sensipar™ (see CLINICAL PHARMACOLOGY , Pharmacokinetics and PRECAUTIONS ). Drug Interactions Sensipar™ is metabolized in part by the enzyme CYP3A4. Co-administration of ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet exposure. Dose adjustment of Sensipar™ may be required and PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, erythromycin, itraconazole; see CLINICAL PHARMACOLOGY , Pharmacokinetics and PRECAUTIONS ). HOW SUPPLIED Sensipar™ 30 mg tablets are formulated as light-green, film-coated, oval-shaped tablets printed with "Amgen" on one side and "30" on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-073-30) Sensipar™ 60 mg tablets are formulated as light-green, film-coated, oval-shaped tablets printed with "Amgen" on one side and "60" on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-074-30) Sensipar™ 90 mg tablets are formulated as light-green, film-coated, oval-shaped tablets printed with "Amgen" on one side and "90" on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-075-30) Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP controlled room temperature]. Rx Only This product, or its use, may be covered by one or more US Patents including US Patent Nos. 6313146, 6211244, 6031003 and 6011068, in addition to others, including patents pending. 钙受体激动剂Sensipar治疗慢性肾衰竭继发性甲状旁腺功能亢进获美国FDA批准上市 继发性甲状旁腺功能亢进症(SHPT)是慢性肾衰竭(CRF)常见的并发症,多发生于肾小球滤过率(GFR)低于80 ml·min-1·1.73 m-23个月以上,是机体对钙、磷、活性维生素D代谢紊乱的一种适应性反应.SHPT可引起肾性骨营养不良、血管和心瓣膜钙化,心血管结构和功能改变使心脏疾病的发病率和病死率增高.SHPT的传统冶疗主要为补充钙剂、磷结合剂、活性维生素D,但只能部分改善甲旁亢,并且可引起高磷血症、高钙血症及钙磷乘积升高等副作用.近年来对钙敏感受体(CaSR)激动剂盐酸西那卡塞特(cinacalcet hydrochloride)的研究取得了较大进展,为SHPT治疗提供了新的选择. Sensipar（cinacalcet HC1）最近获得美国FDA的上市许可证，用于治疗严重慢性肾病综合征。它是一种全新类的口服抗肾病综合征药物。Am－ gen介绍说该药被批准用于肾病透析治疗后所继发产生的高甲状旁腺症（HFT），可降低患者的非正常高钙和磷的浓度。在Sensipar被批准前，惟一可用于治疗继发性高甲状旁腺症的药物为磷酸盐及维生素D甾体类药物等。Sensipar 的作用机制为直接作用于钙敏受体（calcium-sensing recep－ tor），因而它提供了一个有效地临床降钙治疗手段。在有 1100例患者参加的临床试验中，40％接受Sensipar的患者治疗后达到了正常甲状分腺素标准（250pg·mL-1），在降低甲状旁腺素的同时，还降低钙和磷浓度，疗效可维持12个月以上。此外，该药还可以用于甲状旁腺癌的患者，可降低此类患者的高钙浓度。Sensipar不仅对同时服用维生素D的患者有效，对未服用者也有效。该药在服用时，应密切监视血钙浓度。一旦血钙浓度降低至正常范围以下，应采取相应的升钙措施。该药常见的不良反应为恶心和呕吐。 --------------------------------------------------------------- 原产地英文商品名: SENSIPAR 30mg/tablet 30tablets/bottle 原产地英文药品名: cinacalcet HCI 中文参考商品译名: SENSIPAR 30毫克/片 30片/瓶 中文参考药品译名: 盐酸西那卡塞 产地国家: 美国 所属类别: 激素内分泌药物->甲状腺激素类药及抗甲状腺激素药物 处方药:处方药 包装规格: 30毫克/片 30片/瓶 销售单价(美元 US$): 705美元 销售单价(人民币 RMB): 4652元 计价单位: 瓶 --------------------------------------------------------------- 原产地英文商品名: SENSIPAR 60mg/tablet 30tablets/bottle 原产地英文药品名: cinacalcet HCI 中文参考商品译名: SENSIPAR 60毫克/片 30片/瓶 中文参考药品译名: 盐酸西那卡塞 产地国家: 美国 所属类别: 激素内分泌药物->甲状腺激素类药及抗甲状腺激素药物 处方药:处方药 包装规格: 60毫克/片 30片/瓶 销售单价(美元 US$): 1222美元 销售单价(人民币 RMB): 8063 元 计价单位: 瓶 --------------------------------------------------------------- 原产地英文商品名: SENSIPAR 90mg/tablet 30 tablets/bottle 原产地英文药品名: cinacalcet HCI 中文参考商品译名: SENSIPAR 90毫克/片 30片/瓶 中文参考药品译名: 盐酸西那卡塞 产地国家: 美国 所属类别: 激素内分泌药物->甲状腺激素类药及抗甲状腺激素药物 处方药:处方药 包装规格: 90毫克/片 30片/瓶 销售单价(美元 US$): 1815.5美元 销售单价(人民币 RMB): 11984 元 计价单位: 瓶