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帕立骨化醇注射液(胜普乐)说明书如下:

【药品名称】
通用名称：帕立骨化醇注射液
商品名称：胜普乐ZEMPLAR
英文名称：Paricalcitol   Injection

【成份】
胜普乐主要成份为帕立骨化醇。

化学名称：19-去甲-1α,25–二羟维生素D2。
化学机构式：
分子式：C27H44O3
分子量：416.64
辅料：乙醇，丙二醇和注射用水。

【性状】
胜普乐为无色的澄明溶液。

【适应症】用于治疗接受血液透析的慢性肾功能衰竭患者的继发性甲状旁腺功能亢进。

【规格】
（1）1ml：5μg；（2)2ml：10μg

【用法用量】
胜普乐经由血液透析通路给药。
成人
1）起始剂量基于体重：
患者胜普乐推荐的起始剂量为0.04-0.1μg/kg（2.8-7μg），单次注射，给药频率不超过隔日一次，在透析过程中的任何时间给药。
2)剂量调整：
目前在接受透析治疗的终末期肾功能衰竭患者中，可接受的PTH水平目标范围不超过非尿毒症正常范围上限的1.5到3倍。即全段PTH（ipTH)为15.9-31.8pmol/l（150-300pg/ml)。密切监测及个体化剂量调整对于达到合适的生理终点是必要的。如果出现高钙血症或校正后钙磷乘积持续高于52mmol2/l2（65mg2/dl2)。
应减少剂量或中止用药直到这些参数恢复正常。随后，帕立骨化醇的给药剂量应从较低剂量重新开始，如果PTH水平由于治疗而下降，药物剂量可能需要随之减少。
下表为建议的剂量调整方法：

*基线iPH水平指近一次实验室检查的iPH水平
一旦确定了剂量，血清钙和磷应该至少每月检测一次。推荐每三个月检测一次血清iPTH。在帕立骨化醇剂量调整期间，可能需要更加频繁地进行实验室检查。
肝功能不全
在轻度和中度肝功能不全患者体内。未结合的帕立骨化醇浓度与健康受试者相似，因此在这些患者人群中无需进行剂量调整。尚无在重度肝功能不全患者中的应用经验。
儿童患者(0-18岁)
中国儿童患者使用胜普乐的安全性和有效性尚未确定。
老年患者（>65岁）
在帕立骨化醇的Ⅲ期临床研究中，在65岁或超过65岁的患者中应用帕立骨化醇的临床经验有限。在这些研究中，65岁或超过65岁的老年患者与年轻患者相比，在总体安全性和有效性方面未发现差异。

【不良反应】
大约600名患者在Ⅱ/Ⅲ/Ⅳ期临床研究中接受了胜普乐治疗。总的来说，接受胜普乐治疗的患者中有6％报告了不良反应。
与胜普乐治疗有关的常见的不良反应为高钙血症，约在4.7％的患者中发生。高钙血症与过度抑制的PTH的程度有关，能通过适当的剂量调整将其发生风险降至。
按MedDRA系统器官分类、术语及频率列出了至少是可能与帕立骨化醇有关的临床及实验室检查方面的不良事件。采用了以下频率分组：非常常见〔≥1/10〕；常见〔≥1/100，﹤1/10〕；不常见〔≧1/1000，﹤1/100〕；罕见〔≧1/10000，﹤1/1000〕；非常罕见〔﹤1/10000〕，未知〔根据现有数据无法进行估计〕。

【禁忌】
对药品活性成分或任何辅料过敏者。
维生素D中毒。
高钙血症。

【注意事项】
过度地抑制甲状旁腺激素可能导致血清钙水平升高并可能引起代谢性骨病。需对患者进行监测并进行个体化剂量调整，以达到合适的生理终点。
如果出现具有临床显著意义的高钙血症，而患者正在接受某种含钙的磷结合剂，则应减少含钙的磷结合剂的剂量或中止使用含钙的磷结合剂。
慢性高钙血症可能与全身性的血管钙化和其他软组织钙化的发生有关。
任何原因导致的高钙血症均有引起洋地黄中毒的潜在危险，因此，当开具洋地黄与胜普乐合用的处方时应予以谨慎〔参见［药物作用]）。
如果联合应用帕立骨化醇与酮康唑，应予以谨慎(参见［药物相互作用］)。
胜普乐含有20％V/V乙醇（酒精）。每次给药的乙醇含量可达1.3g．可对酒精中毒患者造成损坏。对孕妇或哺乳期间妇女、儿童和高危险人群（如肝病或癫痫患者）应予以重视。
对驾驶和操纵机器能力的影响：未进行胜普乐对驾驶和操纵机器能力影响的研究。
在无相容性研究的情况下，不应将胜普乐与其它药物混合。
丙二醇与肝素会发生相互作用并中和期效应。胜普乐辅料中含丙二醇。故应与肝素采取不同的注射部位给药。
给药前应检查注射液是否有可见微粒无色变化。该溶液为无色的澄明液体。
仅供一次性使用。应将未使用完的丢异。
对于未使用完的产品或废异物。应根据相应得管理办法进行处理。

【孕妇及哺乳期妇女用药】
妊娠：
尚未获得有关帕立骨化醇在妊娠妇女中应用的充足数据。动物研究中已经显示了生殖毒性（参见［药理毒理］）。对于人类的潜在风险尚不明确。除非有明确的必要性，否则胜普乐不应用于妊娠妇女。
哺乳期：
动物研究结果显示少量帕立骨化醇或其代谢产物经乳汁排泄。应综合考虑哺乳对儿童的益处以及帕立骨化醇治疗对妇女的益处以决定是否继续/停止哺乳，或继续/停止帕立骨化醇治疗。

【儿童用药】
中国儿童患者使用胜普乐的安全性和有效性尚未确立。

【老年用药】
参见［用法用量]。

【药物相互作用】
目前尚未对帕立骨化醇注射液进行过药物相互作用的研究。不过，对胜普乐的胶囊制剂行过酮康唑与帕立骨化醇的相互作用研究。
由于高钙血症和钙磷乘积曾高的发生风险可能会增高，磷或维生素D类药物不应与帕立骨化醇和用。
高剂量的含钙制剂或噻嗪类利尿剂可能会增加高钙血症的风险。
由于可能会发生高镁血症，含镁的制剂［如抗酸剂］不应与维生素D类药物合用。
酮康唑是一种已知的针对数种细胞色素P450酶的非特异性抑制剂。现有的体内和体外数据提示酮康唑可能与一些参与帕立骨化醇和其它维生素D类似物的代谢的酶之间存在相互作用。因此，在帕里骨化醇给药期间应慎用酮康唑（参见［注意事项]）。在健康受试者中进行了为期5天，每天两次［BID］、每次200mg的多剂量的同康唑对帕立骨化醇胶囊药物代动力影响，但AUC0-∝约增加了一倍。在使用酮康唑的情况下，帕立骨化醇的平均半衰期为17.0小时，而单独给予帕立骨化醇时则为9.8小时。这项研究结果显示，口服帕立骨化醇之后，有帕立骨化醇与酮康唑药物相互作用导致的帕立骨化醇AUC0-∝增幅不太大可能超过两倍。
任何原因引起的高钙血症都可引起洋地黄中毒，因此，当开具洋地黄与帕立骨化醇合用的处方时应予以谨慎（参见［注意事项]）。

【药物过量】
尚未报道药物过量的病例。
过量使用帕立骨化醇可能导致高钙血症，高磷血症，以及甲状旁腺激素过度抑制［参见［注意事项］)。
一旦出现药物过量。应监测高钙血症（血钙水平)的症状和体征并向医生报告。必要时应给予治疗。
透析对帕立骨化醇并无显著的清除作用。对伴有临床显著意义的高钙血症的患者的治疗包括立即减少帕立骨化醇的治疗剂量或中止用药，同时接受低钙饮食、停用钙补冲剂，鼓励患者活动、注意有无液体和电解质失衡、评估心电图异常[对与接受洋地黄药物的患者极为重要]。并在必要时采用不含钙的透析液进行血液透析和腹膜透析。
当血清钙水平已恢复至正常范围内时，可以较低剂量重新开始使用帕立骨化醇。如果出现持续性的血清钙水平显著升高则需考虑采用其他治疗法。包括使用磷酸盐类药物、皮质激素和利尿。
胜普乐含30％v/v的丙二醇作为辅料。增有与大剂量丙二醇给药有关的毒性反应的个案报告。包括中枢神经系统抑制、溶血和如乳酸中毒。鉴于丙二醇可在透析过程中被清除，使用胜普乐过程中预期不会出现这些事件，但仍需考虑到在药物过量情况下的毒性反应风险。

【临床试验】
对接受透析的CKD5期患者进行了三项为期12周。安慰剂对照的Ⅲ期临床研究，帕立骨化醇的初始给药剂量为每周三次，每次0.04μg/kg．该剂量每两周增加0.04μg/㎏．直至全段甲状旁腺激素〔iPTH〕水平比基线水平将低至少30％或iPTH水平第五次增加使给药剂量增加到0.24μg/kg．或iPTH水平下降低于100Pg/ml。或任意两周内钙磷乘积大于75：或任意时间血清钙水平超过11.5mg/dL。
在六周内帕立骨化醇治疗组患者iPTH水平下降了30％。在上述研究中、帕立骨化醇治疗组与安慰剂对照组高钙血症或高磷血症的发生率并无显著性差异。研究结果如下

一项对164名CKD5期患者进行的长期、开放性、安全性研究（平均给药剂量为每周3次，每次7.5μg）显示，在PTH水平降低（在13个月中平均降低319pg/ml)过程中，平均血清钙、磷水平及钙磷乘积仍可保持在正常的临床范围内。

【药理毒理】
药理作用
帕立骨化醇是一种人工合成的具有生物活性的维生素D类似物，对骨化三醇侧链（D2）和A环（19-ｎｏｒ）进行修饰。临床前研究及体外试验研究显示，帕立骨化醇需通过与维生素D受体（VDR)结合，引发维生素D反应通路的选择活化产生生物学作用。
维生素D与帕立骨化醇可以通过抑制甲状旁腺激素（PTH）的合成与分泌，降低PTH水平。
毒理研究
遗传毒性：帕立骨化醇Ames试验，小鼠淋瘤致畸实验、人类淋巴细胞染色体畸变试验、小鼠微核试验结果均为阴性。
生殖毒性：家免每日一次给予人剂量0.24μg/kg的0.5倍（按体表面积mg/ｍ2计算）的帕立骨化醇，或以人剂量0.24μg/kg的2倍〔按血浆暴露水平计算〕，胎儿的生存率出现轻微下降（5％）。大鼠在20μg/kg〔每周3次，按体便面计算，相当于人剂量0.24μg/kg的13倍〕。由于母体高钙血症导致新生大鼠死亡率明显增加。未观察到对后代发育的影响。在试验剂量下未见致畸作用。
致癌作用
小鼠皮下注射1.3、μg/kg帕里骨化醇（以AUC计相当于0.24μg/kg〕104周。子宫肌瘤及平滑肌肉瘤的发生率增加。10μg/kg组的子宫肌瘤的发生率与对照组相比出现了显著升高。
大鼠皮下注射0.15、0.5、1.5μg/kg帕立骨化醇（以AUC计相当于0.24μg/kg）104周，良性肾上腺嗜铬细胞瘤的发生率增加。大鼠嗜铬细胞瘤发生率增加可能与帕立骨化醇所致的血钙动态平衡有关。
本药为19-去甲-1,25-二羟基维生素D2,是骨化三醇的类似物，属维生素D类抗甲状旁腺药，供静脉或口服用。本药通过选择性激活维生素D的反应途径，抑制甲状旁腺素（PTH）的合成和释放，从而降低PTH水平。其抑制血PTH的疗效与均等剂量的骨化三醇同样有效。在安慰剂对照的研究中，本药诱导高钙血症和高磷血症的倾向降低。健康受试者静脉弹丸式注射单剂0.04μg/kg、0.08μg/kg和0.16μg/kg,注射结束时达血药峰浓度，分别为256pg/ml、664pg/ml和1242pg/ml.帕立骨化醇吸收良好，健康受试者口服0.24μg/g,3小时达血药峰浓度0.63ng/ml,平均*生物利用度约为72％,曲线下面积（AUC0-∞）为5.25（ng.h）/ml,食物对全身生物利用度*影响，但与饮食同服组达峰时间延迟约2小时。静脉给药的曲线下面积（AUC）14.51（ng.h）/ml.99％以上的药物与蛋白结合，稳态分布容积为17~34L.本药经线粒体细胞色素P450（CYP）24、CYP3A4和尿苷二磷酸葡萄糖醛酸转移酶（UGT）1A4广泛代谢，检测到的代谢物为有活性的24（R）-羟基帕立骨化醇。健康受试者中总体清除率为2.5~4L/h,经肾和粪便的排泄率分别为18％~19％和63％~74％,其母体化合物的消除半衰期为4~7小时，血液透析不能清除本药。

【药代动力学】
分布
在需要接受血液透析的慢性肾功能衰竭（CRF）患者中对帕立骨化醇的药带动力学进了研究。帕立骨化醇的给药方式为静脉推注。在以0.04－0.24μg/kg的剂量范围给药后两个小时内，帕立骨化醇的浓度汛速下降；随后，帕立骨化醇的浓度呈对数线性下降。平均半衰期约为15个小时。帕立骨化醇多次给药之后未观察到蓄积现象。
消除　　　　　
在健康受试者中进行了一项研究，该研究采用单次静脉推注剂量0.16μg/kg的3H－帕立骨化醇（ｎ＝4］血浆放射活性源于母体化合物。帕立骨化醇主要经肝胆系统排解途径消除。在粪便中测得74％的放射活性剂量，而尿液中仅有16％。　
代谢
在尿液和粪便中检测到几种未知代谢产物。尿液中未检测到帕立骨化醇。尚未对代谢产物进行特性描述和鉴别。总体上，这些代谢产物约占尿液放射活性的51％和粪便放射活性的59％。帕立骨化醇的体外血浆蛋白结合率很高（﹥99.9％）。在1至100ng/ｍｌ的浓度范围内未出现饱和。

【贮藏】
室温（低于30°C）保存，避免冷冻。

【包装】
I型玻璃安瓿瓶，5支1盒。

【有效期】
24个月

【批准文号】
1ml：5μg： 
2ml：10μg： 

【生产企业】
企业名称：HospiraS.P.A.
生产地址：ViaFosseArdeatine,2-20060Liscate（MI）,Italy

 

 

ZEMPLAR®
(paricalcitol) Injection Fliptop Vial

DESCRIPTION

Paricalcitol, USP, the active ingredient in Zemplar Injection, is a synthetically manufactured analog of calcitriol, the metabolically active form of vitamin D indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease(CKD) Stage 5. Zemplar is available as a sterile, clear, colorless, aqueous solution for intravenous injection. Each mL contains paricalcitol, 2 mcg or 5 mcg and the following inactive ingredients: alcohol, 20% (v/v) and propylene glycol, 30% (v/v).

Paricalcitol is a white powder chemically designated as 19-nor-1α,3β,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)-triene and has the following structural formula:

Molecular formula is C27H44O3.

Molecular weight is 416.64.

Indications & Dosage

INDICATIONS

Zemplar is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease Stage 5.

DOSAGE AND ADMINISTRATION

The currently accepted target range for iPTH levels in CKD Stage 5 patients is no more than 1.5 to 3 times the non-uremic upper limit of normal.

The recommended initial dose of Zemplar is 0.04 mcg/kg to 0.1 mcg/kg (2.8 – 7 mcg) administered as a bolus dose no more frequently than every other day at any time during dialysis.

If a satisfactory response is not observed, the dose may be increased by 2 to 4 mcg at 2- to 4-week intervals. During any dose adjustment period, serum calcium and phosphorus levels should be monitored more frequently, and if an elevated calcium level or a Ca × P product greater than 75 is noted, the drug dosage should be immediately reduced or interrupted until these parameters are normalized. Then, Zemplar should be reinitiated at a lower dose. If a patient is on a calcium-based phosphate binder, the dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. Zemplar doses may need to be decreased as the PTH levels decrease in response to therapy. Thus, incremental dosing must be individualized.

The following table is a suggested approach in dose titration:

Suggested Dosing Guidelines

The influence of mild to moderately impaired hepatic function on paricalcitol pharmacokinetics is sufficiently small that no dosing adjustment is required.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

After initial vial use, the contents of the multi-dose vial remain stable up to seven days when stored at controlled room temperature (see HOW SUPPLIED). Discard unused portion of the single-dose vial.

HOW SUPPLIED

Zemplar Injection is available as 2 mcg/mL (NDC 0074-4637-01) and 5 mcg/mL (NDC 0074-1658-01 and NDC 0074–1658–05) in trays of 25 vials.

Store at 25°C (77°F). Excursions permitted between 15° - 30°C (59° - 86°F).

Manufactured for: AbbVie Inc., North Chicago, IL 60064, U.S.A. Revised: July, 2013.

Indications & Dosage

INDICATIONS

Zemplar is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease Stage 5.

DOSAGE AND ADMINISTRATION

The currently accepted target range for iPTH levels in CKD Stage 5 patients is no more than 1.5 to 3 times the non-uremic upper limit of normal.

The recommended initial dose of Zemplar is 0.04 mcg/kg to 0.1 mcg/kg (2.8 – 7 mcg) administered as a bolus dose no more frequently than every other day at any time during dialysis.

If a satisfactory response is not observed, the dose may be increased by 2 to 4 mcg at 2- to 4-week intervals. During any dose adjustment period, serum calcium and phosphorus levels should be monitored more frequently, and if an elevated calcium level or a Ca × P product greater than 75 is noted, the drug dosage should be immediately reduced or interrupted until these parameters are normalized. Then, Zemplar should be reinitiated at a lower dose. If a patient is on a calcium-based phosphate binder, the dose may be decreased or withheld, or the patient may be switched to a non-calcium-based phosphate binder. Zemplar doses may need to be decreased as the PTH levels decrease in response to therapy. Thus, incremental dosing must be individualized.

The following table is a suggested approach in dose titration:

Suggested Dosing Guidelines

The influence of mild to moderately impaired hepatic function on paricalcitol pharmacokinetics is sufficiently small that no dosing adjustment is required.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

After initial vial use, the contents of the multi-dose vial remain stable up to seven days when stored at controlled room temperature (see HOW SUPPLIED). Discard unused portion of the single-dose vial.

HOW SUPPLIED

Zemplar Injection is available as 2 mcg/mL (NDC 0074-4637-01) and 5 mcg/mL (NDC 0074-1658-01 and NDC 0074–1658–05) in trays of 25 vials.

Store at 25°C (77°F). Excursions permitted between 15° - 30°C (59° - 86°F).

Manufactured for: AbbVie Inc., North Chicago, IL 60064, U.S.A. Revised: July, 2013.

Side Effects

SIDE EFFECTS

Zemplar has been evaluated for safety in clinical studies in 609 CKD Stage 5 patients. In four, placebocontrolled, double-blind, multicenter studies, discontinuation of therapy due to any adverse event occurred in 6.5% of 62 patients treated with Zemplar (dosage titrated as tolerated, see Clinical Studies) and 2.0% of 51 patients treated with placebo for 1 to 3 months. Adverse events occurring in the Zemplar group at a frequency of 2% or greater and with an incidence greater than that in the placebo group, regardless of causality, are presented in the following table:

Adverse Event Incidence Rates for All Treated Patients In All Placebo-Controlled Studies

A patient who reported the same medical term more than once was counted only once for that medical term.

Safety parameters (changes in mean Ca, P, Ca × P) in an open-label safety study up to 13 months in duration support the long-term safety of Zemplar in this patient population (see Clinical Studies).

Other Adverse Reactions Observed During Clinical Evaluation Of Zemplar Injection

The following adverse reactions, with a causal relationship to Zemplar, occurred in < 2% of the Zemplar treated patients in the above double-blind, placebo-controlled clinical trial data set. In addition,the following also includes adverse reactions reported in Zemplar-treated patients who participated in other studies (non placebo-controlled), including double-blind, active-controlled and open-label studies:

Blood and Lymphatic System Disorders:

Anemia, lymphadenopathy

Cardiac Disorders:

Arrhythmia, atrial flutter, cardiac arrest

Ear and Labyrinth Disorders:

Ear discomfort

Endocrine Disorders:

Hyperparathyroidism, hypoparathyroidism

Eye Disorders:

Conjunctivitis, glaucoma, ocular hyperemia

Gastrointestinal Disorders:

Abdominal discomfort, constipation, diarrhea, dysphagia, gastritis, intestinal ischemia, rectalhemorrhage

General Disorders and Administration Site Conditions:

Asthenia, chest discomfort, chest pain, condition aggravated, edema peripheral, fatigue, feeling abnormal, gait disturbance, injection site extravasation, injection site pain, pain, swelling, thirst

Infections and Infestations:

Nasopharyngitis, upper respiratory tract infection, vaginal infection

Investigations:

Aspartate aminotransferase increased, bleeding time prolonged, heart rate irregular, laboratory test abnormal, weight decreased

Metabolism and Nutrition Disorders:

Decreased appetite, hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia

Musculoskeletal and Connective Tissue Disorders:

Joint stiffness, muscle twitching, myalgia

Neoplasms Benign, Malignant and Unspecified:

Breast cancer

Nervous System Disorders:

Cerebrovascular accident, dizziness, dysgeusia, headache, hypoesthesia, myoclonus, paresthesia, syncope, unresponsive to stimuli

Psychiatric Disorders:

Agitation, confusional state, delirium, insomnia, nervousness, restlessness

Reproductive System and Breast Disorders:

Breast pain, erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders:

Cough, dyspnea, orthopnea, pulmonary edema, wheezing

Skin and Subcutaneous Tissue Disorders:

Alopecia, blister, hirsutism, night sweats, rash pruritic, pruritus, skin burning sensation

Vascular Disorders:

Hypertension, hypotension

Additional Adverse Events Reported During Post-marketing Experience

Allergic reactions, such as rash, urticaria, and angioedema (including laryngeal edema) have been reported.

Drug Interactions

DRUG INTERACTIONS

Specific interaction studies were not performed with Zemplar Injection. Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A nor induce the clearance of drug metabolized by CYP2B6, CYP2C9 or CYP3A.

A multiple dose drug-drug interaction study with ketoconazole and paricalcitol capsule demonstrated that ketoconazole approximately doubled paricalcitol AUC0-∞ (see CLINICAL PHARMACOLOGY). Since paricalcitol is partially metabolized by CYP3A and ketoconazole is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while paricalcitol is co-administered with ketoconazole and other strong P450 3A inhibitors including the following drugs but not limited to: atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole.

Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar.

Side Effects

SIDE EFFECTS

Zemplar has been evaluated for safety in clinical studies in 609 CKD Stage 5 patients. In four, placebocontrolled, double-blind, multicenter studies, discontinuation of therapy due to any adverse event occurred in 6.5% of 62 patients treated with Zemplar (dosage titrated as tolerated, see Clinical Studies) and 2.0% of 51 patients treated with placebo for 1 to 3 months. Adverse events occurring in the Zemplar group at a frequency of 2% or greater and with an incidence greater than that in the placebo group, regardless of causality, are presented in the following table:

Adverse Event Incidence Rates for All Treated Patients In All Placebo-Controlled Studies

A patient who reported the same medical term more than once was counted only once for that medical term.

Safety parameters (changes in mean Ca, P, Ca × P) in an open-label safety study up to 13 months in duration support the long-term safety of Zemplar in this patient population (see Clinical Studies).

Other Adverse Reactions Observed During Clinical Evaluation Of Zemplar Injection

The following adverse reactions, with a causal relationship to Zemplar, occurred in < 2% of the Zemplar treated patients in the above double-blind, placebo-controlled clinical trial data set. In addition,the following also includes adverse reactions reported in Zemplar-treated patients who participated in other studies (non placebo-controlled), including double-blind, active-controlled and open-label studies:

Blood and Lymphatic System Disorders:

Anemia, lymphadenopathy

Cardiac Disorders:

Arrhythmia, atrial flutter, cardiac arrest

Ear and Labyrinth Disorders:

Ear discomfort

Endocrine Disorders:

Hyperparathyroidism, hypoparathyroidism

Eye Disorders:

Conjunctivitis, glaucoma, ocular hyperemia

Gastrointestinal Disorders:

Abdominal discomfort, constipation, diarrhea, dysphagia, gastritis, intestinal ischemia, rectalhemorrhage

General Disorders and Administration Site Conditions:

Asthenia, chest discomfort, chest pain, condition aggravated, edema peripheral, fatigue, feeling abnormal, gait disturbance, injection site extravasation, injection site pain, pain, swelling, thirst

Infections and Infestations:

Nasopharyngitis, upper respiratory tract infection, vaginal infection

Investigations:

Aspartate aminotransferase increased, bleeding time prolonged, heart rate irregular, laboratory test abnormal, weight decreased

Metabolism and Nutrition Disorders:

Decreased appetite, hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia

Musculoskeletal and Connective Tissue Disorders:

Joint stiffness, muscle twitching, myalgia

Neoplasms Benign, Malignant and Unspecified:

Breast cancer

Nervous System Disorders:

Cerebrovascular accident, dizziness, dysgeusia, headache, hypoesthesia, myoclonus, paresthesia, syncope, unresponsive to stimuli

Psychiatric Disorders:

Agitation, confusional state, delirium, insomnia, nervousness, restlessness

Reproductive System and Breast Disorders:

Breast pain, erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders:

Cough, dyspnea, orthopnea, pulmonary edema, wheezing

Skin and Subcutaneous Tissue Disorders:

Alopecia, blister, hirsutism, night sweats, rash pruritic, pruritus, skin burning sensation

Vascular Disorders:

Hypertension, hypotension

Additional Adverse Events Reported During Post-marketing Experience

Allergic reactions, such as rash, urticaria, and angioedema (including laryngeal edema) have been reported.

Drug Interactions

DRUG INTERACTIONS

Specific interaction studies were not performed with Zemplar Injection. Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A nor induce the clearance of drug metabolized by CYP2B6, CYP2C9 or CYP3A.

A multiple dose drug-drug interaction study with ketoconazole and paricalcitol capsule demonstrated that ketoconazole approximately doubled paricalcitol AUC0-∞ (see CLINICAL PHARMACOLOGY). Since paricalcitol is partially metabolized by CYP3A and ketoconazole is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while paricalcitol is co-administered with ketoconazole and other strong P450 3A inhibitors including the following drugs but not limited to: atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole.

Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar.

Warnings

WARNINGS

Acute overdose of Zemplar may cause hypercalcemia, and require emergency attention (see OVERDOSAGE). During dose adjustment, serum calcium and phosphorus levels should be monitored closely (e.g., twice weekly). If clinically significant hypercalcemia develops, the dose should be reduced or interrupted. Chronic administration of Zemplar may place patients at risk of hypercalcemia, elevated Ca × P product, and metastatic calcification. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification.

Concomitant administration of high doses of calcium-containing preparations or thiazide diueretics with Zemplar may increase the risk of hypercalcemia. High intake of calcium and phosphate concomitant with vitamin D compounds may lead to serum abnormalities requiring more frequent patient monitoring and individualized dose titration. Patients also should be informed about the symptoms of elevated calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss.

Prescription-based doses of vitamin D and its derivatives should be withheld during Zemplar treatment to avoid hypercalcemia.

Aluminum-containing preparations (e.g., antacids, phosphate binders) should not be administered chronically with Zemplar, as increased blood levels of aluminum and aluminum bone toxicity may occur.

Precautions

PRECAUTIONSGeneral

Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar. Adynamic bone lesions may develop if PTH levels are suppressed to abnormal levels.

Laboratory Tests

During the initial phase of medication, serum calcium and phosphorus should be determined frequently (e.g., twice weekly). Once dosage has been established, serum calcium and phosphorus should be measured at least monthly. Measurements of serum or plasma PTH are recommended every 3 months. During dose adjustment of Zemplar, laboratory tests may be required more frequently.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 104-week carcinogenicity study in CD-1 mice, an increased incidence of uterine leiomyoma and leiomyosarcoma was observed at subcutaneous doses of 1, 3, 10 mcg/kg (2 to 15 times the AUC at a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The incidence rate of uterine leiomyoma was significantly different than the control group at the highest dose of 10 mcg/kg.

In a 104-week carcinogenicity study in rats, there was an increased incidence of benign adrenal pheochromocytoma at subcutaneous doses of 0.15, 0.5, 1.5 mcg/kg ( < 1 to 7 times the exposure following a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The increased incidence of pheochromocytomas in rats may be related to the alteration of calcium homeostasis by paricalcitol.

Paricalcitol did not exhibit genetic toxicity in vitro with or without metabolic activation in the microbial mutagenesis assay (Ames Assay), mouse lymphoma mutagenesis assay (L5178Y), or a human lymphocyte cell chromosomal aberration assay. There was also no evidence of genetic toxicity in an in vivo mouse micronucleus assay. Zemplar had no effect on fertility (male or female) in rats at intravenous doses up to 20 mcg/kg/dose [equivalent to 13 times the highest recommended human dose (0.24 mcg/kg) based on surface area, mg/m²].

PregnancyPregnancy Category C

Paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at a dose 0.5 times the 0.24 mcg/kg human dose (based on surface area, mg/m²) and when administered to rats at a dose 2 times the 0.24 mcg/kg human dose (based on plasma levels of exposure). At the highest dose tested (20 mcg/kg 3 times per week in rats, 13 times the 0.24 mcg/kg human dose based on surface area), there was a significant increase of the mortality of newborn rats at doses that were maternally toxic (hypercalcemia). No other effects on offspring development were observed. Paricalcitol was not teratogenic at the doses tested.

There are no adequate and well-controlled studies in pregnant women. Zemplar should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Mothers

Studies in rats have shown that paricalcitol is present in the milk. It is not known whether paricalcitol is excreted in human milk. In the nursing patient, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Zemplar were examined in a 12-week randomized, double-blind, placebo-controlled study of 29 pediatric patients, aged 5-19 years, with end-stage renal disease on hemodialysis and nearly all had received some form of vitamin D prior to the study. Seventy-six percent of the patients were male, 52% were Caucasian and 45% were African-American. The initial dose of Zemplar was 0.04 mcg/kg 3 times per week based on baseline iPTH level of less than 500 pg/mL, or 0.08 mcg/kg 3 times a week, based on baseline iPTH level of ≥ 500 pg/mL, respectively. The dose of Zemplar was adjusted in 0.04 mcg/kg increments based on the levels of serum iPTH, calcium and Ca x P. The mean baseline levels of iPTH were 841 pg/mL for the 15 Zemplar-treated patients and 740 pg/mL for the 14 placebo-treated subjects. The mean dose of Zemplar administered was 4.6 mcg (range: 0.8 mcg – 9.6 mcg). Ten of the 15 (67%) Zemplar-treated patients and 2 of the 14 (14%) placebo-treated patients completed the trial. Ten of the placebo patients (71%) were discontinued due to excessive elevations in iPTH levels as defined by 2 consecutive iPTH levels > 700 pg/mL and greater than baseline after 4 weeks of treatment.

In the primary efficacy analysis, 9 of 15 (60%) subjects in the Zemplar group had 2 consecutive 30% decreases from baseline iPTH compared with 3 of 14 (21%) patients in the placebo group (95% CI for the difference between groups –1%, 63%). Twenty-three percent of Zemplar vs. 31% of placebo patients had at least one serum calcium level > 10.3 mg/dL, and 40% vs. 14% of Zemplar vs. placebo subjects had at least one Ca x P ion product > 72 (mg/dL)2. The overall percentage of serum calcium measurements > 10.3 mg/dL was 7% in the Zemplar group and 7% in the placebo group; the overall percentage of patients with Ca x P product > 72 (mg/dL)2 was 8% in the Zemplar group and 7% in the placebo group. No subjects in either the Zemplar group or placebo group developed hypercalcemia (defined as at least one calcium value > 11.2 mg/dL) during the study.

Geriatric Use

Of the 40 patients receiving Zemplar in the three phase 3 placebo-controlled CKD Stage 5 studies, 10 patients were 65 years or over. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients.

Warnings

WARNINGS

Acute overdose of Zemplar may cause hypercalcemia, and require emergency attention (see OVERDOSAGE). During dose adjustment, serum calcium and phosphorus levels should be monitored closely (e.g., twice weekly). If clinically significant hypercalcemia develops, the dose should be reduced or interrupted. Chronic administration of Zemplar may place patients at risk of hypercalcemia, elevated Ca × P product, and metastatic calcification. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification.

Concomitant administration of high doses of calcium-containing preparations or thiazide diueretics with Zemplar may increase the risk of hypercalcemia. High intake of calcium and phosphate concomitant with vitamin D compounds may lead to serum abnormalities requiring more frequent patient monitoring and individualized dose titration. Patients also should be informed about the symptoms of elevated calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss.

Prescription-based doses of vitamin D and its derivatives should be withheld during Zemplar treatment to avoid hypercalcemia.

Aluminum-containing preparations (e.g., antacids, phosphate binders) should not be administered chronically with Zemplar, as increased blood levels of aluminum and aluminum bone toxicity may occur.

Precautions

PRECAUTIONSGeneral

Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar. Adynamic bone lesions may develop if PTH levels are suppressed to abnormal levels.

Laboratory Tests

During the initial phase of medication, serum calcium and phosphorus should be determined frequently (e.g., twice weekly). Once dosage has been established, serum calcium and phosphorus should be measured at least monthly. Measurements of serum or plasma PTH are recommended every 3 months. During dose adjustment of Zemplar, laboratory tests may be required more frequently.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 104-week carcinogenicity study in CD-1 mice, an increased incidence of uterine leiomyoma and leiomyosarcoma was observed at subcutaneous doses of 1, 3, 10 mcg/kg (2 to 15 times the AUC at a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The incidence rate of uterine leiomyoma was significantly different than the control group at the highest dose of 10 mcg/kg.

In a 104-week carcinogenicity study in rats, there was an increased incidence of benign adrenal pheochromocytoma at subcutaneous doses of 0.15, 0.5, 1.5 mcg/kg ( < 1 to 7 times the exposure following a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The increased incidence of pheochromocytomas in rats may be related to the alteration of calcium homeostasis by paricalcitol.

Paricalcitol did not exhibit genetic toxicity in vitro with or without metabolic activation in the microbial mutagenesis assay (Ames Assay), mouse lymphoma mutagenesis assay (L5178Y), or a human lymphocyte cell chromosomal aberration assay. There was also no evidence of genetic toxicity in an in vivo mouse micronucleus assay. Zemplar had no effect on fertility (male or female) in rats at intravenous doses up to 20 mcg/kg/dose [equivalent to 13 times the highest recommended human dose (0.24 mcg/kg) based on surface area, mg/m²].

PregnancyPregnancy Category C

Paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at a dose 0.5 times the 0.24 mcg/kg human dose (based on surface area, mg/m²) and when administered to rats at a dose 2 times the 0.24 mcg/kg human dose (based on plasma levels of exposure). At the highest dose tested (20 mcg/kg 3 times per week in rats, 13 times the 0.24 mcg/kg human dose based on surface area), there was a significant increase of the mortality of newborn rats at doses that were maternally toxic (hypercalcemia). No other effects on offspring development were observed. Paricalcitol was not teratogenic at the doses tested.

There are no adequate and well-controlled studies in pregnant women. Zemplar should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Mothers

Studies in rats have shown that paricalcitol is present in the milk. It is not known whether paricalcitol is excreted in human milk. In the nursing patient, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Zemplar were examined in a 12-week randomized, double-blind, placebo-controlled study of 29 pediatric patients, aged 5-19 years, with end-stage renal disease on hemodialysis and nearly all had received some form of vitamin D prior to the study. Seventy-six percent of the patients were male, 52% were Caucasian and 45% were African-American. The initial dose of Zemplar was 0.04 mcg/kg 3 times per week based on baseline iPTH level of less than 500 pg/mL, or 0.08 mcg/kg 3 times a week, based on baseline iPTH level of ≥ 500 pg/mL, respectively. The dose of Zemplar was adjusted in 0.04 mcg/kg increments based on the levels of serum iPTH, calcium and Ca x P. The mean baseline levels of iPTH were 841 pg/mL for the 15 Zemplar-treated patients and 740 pg/mL for the 14 placebo-treated subjects. The mean dose of Zemplar administered was 4.6 mcg (range: 0.8 mcg – 9.6 mcg). Ten of the 15 (67%) Zemplar-treated patients and 2 of the 14 (14%) placebo-treated patients completed the trial. Ten of the placebo patients (71%) were discontinued due to excessive elevations in iPTH levels as defined by 2 consecutive iPTH levels > 700 pg/mL and greater than baseline after 4 weeks of treatment.

In the primary efficacy analysis, 9 of 15 (60%) subjects in the Zemplar group had 2 consecutive 30% decreases from baseline iPTH compared with 3 of 14 (21%) patients in the placebo group (95% CI for the difference between groups –1%, 63%). Twenty-three percent of Zemplar vs. 31% of placebo patients had at least one serum calcium level > 10.3 mg/dL, and 40% vs. 14% of Zemplar vs. placebo subjects had at least one Ca x P ion product > 72 (mg/dL)2. The overall percentage of serum calcium measurements > 10.3 mg/dL was 7% in the Zemplar group and 7% in the placebo group; the overall percentage of patients with Ca x P product > 72 (mg/dL)2 was 8% in the Zemplar group and 7% in the placebo group. No subjects in either the Zemplar group or placebo group developed hypercalcemia (defined as at least one calcium value > 11.2 mg/dL) during the study.

Geriatric Use

Of the 40 patients receiving Zemplar in the three phase 3 placebo-controlled CKD Stage 5 studies, 10 patients were 65 years or over. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients.

Overdosage & Contraindications

OVERDOSE

Overdosage of Zemplar may lead to hypercalcemia, hypercalciuria, hyperphosphatemia, and over suppression of PTH. (see WARNINGS).

Treatment Of Overdosage And Hypercalcemia

The treatment of acute overdosage should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and institution of a low calcium diet are also indicated in acute overdosage.

General treatment of hypercalcemia due to overdosage consists of immediate dose reduction or suspension of Zemplar therapy, institution of a low calcium diet, withdrawal of calcium supplements, patient mobilization, and attention to fluid and electrolyte imbalances. Serum calcium levels should be determined at least weekly until normocalcemia ensues. When serum calcium levels have returned to within normal limits, Zemplar may be reinitiated at a lower dose. If persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives that may be considered. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce diuresis. Also, one may consider dialysis against a calcium-free dialysate.

Zemplar is not significantly removed by dialysis.

CONTRAINDICATIONS

Zemplar should not be given to patients with evidence of vitamin D toxicity, hypercalcemia, or hypersensitivity to any ingredient in this product (see WARNINGS).

Overdosage & Contraindications

OVERDOSE

Overdosage of Zemplar may lead to hypercalcemia, hypercalciuria, hyperphosphatemia, and over suppression of PTH. (see WARNINGS).

Treatment Of Overdosage And Hypercalcemia

The treatment of acute overdosage should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and institution of a low calcium diet are also indicated in acute overdosage.

General treatment of hypercalcemia due to overdosage consists of immediate dose reduction or suspension of Zemplar therapy, institution of a low calcium diet, withdrawal of calcium supplements, patient mobilization, and attention to fluid and electrolyte imbalances. Serum calcium levels should be determined at least weekly until normocalcemia ensues. When serum calcium levels have returned to within normal limits, Zemplar may be reinitiated at a lower dose. If persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives that may be considered. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce diuresis. Also, one may consider dialysis against a calcium-free dialysate.

Zemplar is not significantly removed by dialysis.

CONTRAINDICATIONS

Zemplar should not be given to patients with evidence of vitamin D toxicity, hypercalcemia, or hypersensitivity to any ingredient in this product (see WARNINGS).

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Secondary hyperparathyroidism is characterized by an elevation in parathyroid hormone (PTH) associated with inadequate levels of active vitamin D hormone. The source of vitamin D in the body is from synthesis in the skin and from dietary intake. Vitamin D requires two sequential hydroxylations in the liver and the kidney to bind to and to activate the vitamin D receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH)2D3], is a hormone that binds to VDRs that are present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis, and to VDRs found in many other tissues, including prostate, endothelium and immune cells. VDR activation is essential for the proper formation and maintenance of normal bone. In the diseased kidney, the activation of vitamin D is diminished, resulting in a rise of PTH, subsequently leading to secondary hyperparathyroidism, and disturbances in the calcium and phosphorus homeostasis. The decreased levels of 1,25(OH)2D3 and resultant elevated PTH levels, both of which often precede abnormalities in serum calcium and phosphorus, affect bone turnover rate and may result in renal osteodystrophy.

Mechanism Of Action

Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the VDR, which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.

Pharmacokinetics

Within two hours after administering Zemplar intravenous doses ranging from 0.04 to 0.24 mcg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined loglinearly. No accumulation of paricalcitol was observed with three times a week dosing.

Distribution

Paricalcitol is extensively bound to plasma proteins ( ≥ 99.8%). In healthy subjects, the steady state volume of distribution is approximately 23.8 L. The mean volume of distribution following a 0.24 mcg/kg dose of paricalcitol in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD) is between 31 and 35 L.

Metabolism

After IV administration of a 0.48 mcg/kg dose of 3H-paricalcitol, parent drug was extensively metabolized, with only about 2% of the dose eliminated unchanged in the feces and no parent drug found in the urine. Several metabolites were detected in both the urine and feces. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression.

In vitro data suggest that paricalcitol is metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24(R)-hydroxylation (present at low levels in plasma), as well as 24,26- and 24,28- dihydroxylation and direct glucuronidation.

Elimination

Paricalcitol is excreted primarily by hepatobiliary excretion. Approximately 63% of the radioactivity was eliminated in the feces and 19% was recovered in the urine in healthy subjects. In healthy subjects, the mean elimination half-life of paricalcitol is about five to seven hours over the studied dose range of 0.04 to 0.16 mcg/kg. The pharmacokinetics of paricalcitol has been studied in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD). The mean elimination half-life of paricalcitol after administration of 0.24 mcg/kg paricalcitol IV bolus dose in CKD Stage 5 HD and PD patients is 13.9 and 15.4 hours, respectively (Table 1).

Table 1 : Mean ± SD Paricalcitol Pharmacokinetic Parameters in CKD Stage 5 Subjects Following Single 0.24 mcg/kg IV Bolus Dose

No accumulation of paricalcitol was observed with three times a week dosing which is consistent with the observed half-life.

Special PopulationsGeriatric

The pharmacokinetics of paricalcitol have not been investigated in geriatric patients greater than 65 years.

Pediatrics

The pharmacokinetics of paricalcitol have not been investigated in patients less than 18 years of age.

Gender

The pharmacokinetics of paricalcitol were gender independent.

Hepatic Impairment

The disposition of paricalcitol (0.24 mcg/kg) was compared in patients with mild (n=5) and moderate (n=5) hepatic impairment (as indicated by the Child-Pugh method) and subjects with normal hepatic function (n=10). The pharmacokinetics of unbound paricalcitol were similar across the range of hepatic function evaluated in this study. No dose adjustment is required in patients with mild and moderate hepatic impairment. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.

Renal Impairment

The pharmacokinetics of paricalcitol have been studied in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD). Hemodialysis procedure has essentially no effect on paricalcitol elimination. However, compared to healthy subjects, CKD Stage 5 subjects showed a decreased CL and increased half-life (see Pharmacokinetics -Elimination).

Drug Interactions

An in vitro study indicates that paricalcitol is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A at concentrations up to 50 nM (21 ng/mL) (approximately 20-fold greater than that obtained after highest tested dose). In fresh primary cultured hepatocytes, the induction observed at paricalcitol concentrations up to 50 nM was less than two-fold for CYP2B6, CYP2C9 or CYP3A, where the positive controls rendered a six- to nineteen-fold induction. Hence, paricalcitol is not expected to inhibit or induce the clearance of drugs metabolized by these enzymes.

Drug interactions with paricalcitol injection have not been studied.

Omeprazole

The pharmacokinetic interaction between paricalcitol capsule (16 mcg) and omeprazole (40 mg; oral), a strong inhibitor of CYP2C19, was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol were unaffected when omeprazole was administrated approximately 2 hours prior to the paricalcitol dose.

Ketoconazole

Although no data are available for the drug interaction between paricalcitol injection and ketoconazole, a strong inhibitor of CYP3A, the effect of multiple doses of ketoconazole administered as 200 mg BID for 5 days on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The Cmax of paricalcitol was minimally affected, but AUC0-∞ approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone (SeePRECAUTIONS).

Clinical Studies

In three 12-week, placebo-controlled, phase 3 studies in chronic kidney disease Stage 5 patients on dialysis, the dose of Zemplar was started at 0.04 mcg/kg 3 times per week. The dose was increased by 0.04 mcg/kg every 2 weeks until intact parathyroid hormone (iPTH) levels were decreased at least 30% from baseline or a fifth escalation brought the dose to 0.24 mcg/kg, or iPTH fell to less than 100 pg/mL, or the Ca × P product was greater than 75 within any 2 week period, or serum calcium became greater than 11.5 mg/dL at any time.

Patients treated with Zemplar achieved a mean iPTH reduction of 30% within 6 weeks. In these studies, there was no significant difference in the incidence of hypercalcemia or hyperphosphatemiabetween Zemplar and placebo-treated patients. The results from these studies are as follows:

A long-term, open-label safety study of 164 CKD Stage 5 patients (mean dose of 7.5 mcg three times per week), demonstrated that mean serum Ca, P, and Ca × P remained within clinically appropriate ranges with PTH reduction (mean decrease of 319 pg/mL at 13 months).

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Secondary hyperparathyroidism is characterized by an elevation in parathyroid hormone (PTH) associated with inadequate levels of active vitamin D hormone. The source of vitamin D in the body is from synthesis in the skin and from dietary intake. Vitamin D requires two sequential hydroxylations in the liver and the kidney to bind to and to activate the vitamin D receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH)2D3], is a hormone that binds to VDRs that are present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis, and to VDRs found in many other tissues, including prostate, endothelium and immune cells. VDR activation is essential for the proper formation and maintenance of normal bone. In the diseased kidney, the activation of vitamin D is diminished, resulting in a rise of PTH, subsequently leading to secondary hyperparathyroidism, and disturbances in the calcium and phosphorus homeostasis. The decreased levels of 1,25(OH)2D3 and resultant elevated PTH levels, both of which often precede abnormalities in serum calcium and phosphorus, affect bone turnover rate and may result in renal osteodystrophy.

Mechanism Of Action

Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the VDR, which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.

Pharmacokinetics

Within two hours after administering Zemplar intravenous doses ranging from 0.04 to 0.24 mcg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined loglinearly. No accumulation of paricalcitol was observed with three times a week dosing.

Distribution

Paricalcitol is extensively bound to plasma proteins ( ≥ 99.8%). In healthy subjects, the steady state volume of distribution is approximately 23.8 L. The mean volume of distribution following a 0.24 mcg/kg dose of paricalcitol in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD) is between 31 and 35 L.

Metabolism

After IV administration of a 0.48 mcg/kg dose of 3H-paricalcitol, parent drug was extensively metabolized, with only about 2% of the dose eliminated unchanged in the feces and no parent drug found in the urine. Several metabolites were detected in both the urine and feces. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression.

In vitro data suggest that paricalcitol is metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24(R)-hydroxylation (present at low levels in plasma), as well as 24,26- and 24,28- dihydroxylation and direct glucuronidation.

Elimination

Paricalcitol is excreted primarily by hepatobiliary excretion. Approximately 63% of the radioactivity was eliminated in the feces and 19% was recovered in the urine in healthy subjects. In healthy subjects, the mean elimination half-life of paricalcitol is about five to seven hours over the studied dose range of 0.04 to 0.16 mcg/kg. The pharmacokinetics of paricalcitol has been studied in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD). The mean elimination half-life of paricalcitol after administration of 0.24 mcg/kg paricalcitol IV bolus dose in CKD Stage 5 HD and PD patients is 13.9 and 15.4 hours, respectively (Table 1).

Table 1 : Mean ± SD Paricalcitol Pharmacokinetic Parameters in CKD Stage 5 Subjects Following Single 0.24 mcg/kg IV Bolus Dose

No accumulation of paricalcitol was observed with three times a week dosing which is consistent with the observed half-life.

Special PopulationsGeriatric

The pharmacokinetics of paricalcitol have not been investigated in geriatric patients greater than 65 years.

Pediatrics

The pharmacokinetics of paricalcitol have not been investigated in patients less than 18 years of age.

Gender

The pharmacokinetics of paricalcitol were gender independent.

Hepatic Impairment

The disposition of paricalcitol (0.24 mcg/kg) was compared in patients with mild (n=5) and moderate (n=5) hepatic impairment (as indicated by the Child-Pugh method) and subjects with normal hepatic function (n=10). The pharmacokinetics of unbound paricalcitol were similar across the range of hepatic function evaluated in this study. No dose adjustment is required in patients with mild and moderate hepatic impairment. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.

Renal Impairment

The pharmacokinetics of paricalcitol have been studied in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD). Hemodialysis procedure has essentially no effect on paricalcitol elimination. However, compared to healthy subjects, CKD Stage 5 subjects showed a decreased CL and increased half-life (see Pharmacokinetics -Elimination).

Drug Interactions

An in vitro study indicates that paricalcitol is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A at concentrations up to 50 nM (21 ng/mL) (approximately 20-fold greater than that obtained after highest tested dose). In fresh primary cultured hepatocytes, the induction observed at paricalcitol concentrations up to 50 nM was less than two-fold for CYP2B6, CYP2C9 or CYP3A, where the positive controls rendered a six- to nineteen-fold induction. Hence, paricalcitol is not expected to inhibit or induce the clearance of drugs metabolized by these enzymes.

Drug interactions with paricalcitol injection have not been studied.

Omeprazole

The pharmacokinetic interaction between paricalcitol capsule (16 mcg) and omeprazole (40 mg; oral), a strong inhibitor of CYP2C19, was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol were unaffected when omeprazole was administrated approximately 2 hours prior to the paricalcitol dose.

Ketoconazole

Although no data are available for the drug interaction between paricalcitol injection and ketoconazole, a strong inhibitor of CYP3A, the effect of multiple doses of ketoconazole administered as 200 mg BID for 5 days on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The Cmax of paricalcitol was minimally affected, but AUC0-∞ approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone (SeePRECAUTIONS).

Clinical Studies

In three 12-week, placebo-controlled, phase 3 studies in chronic kidney disease Stage 5 patients on dialysis, the dose of Zemplar was started at 0.04 mcg/kg 3 times per week. The dose was increased by 0.04 mcg/kg every 2 weeks until intact parathyroid hormone (iPTH) levels were decreased at least 30% from baseline or a fifth escalation brought the dose to 0.24 mcg/kg, or iPTH fell to less than 100 pg/mL, or the Ca × P product was greater than 75 within any 2 week period, or serum calcium became greater than 11.5 mg/dL at any time.

Patients treated with Zemplar achieved a mean iPTH reduction of 30% within 6 weeks. In these studies, there was no significant difference in the incidence of hypercalcemia or hyperphosphatemiabetween Zemplar and placebo-treated patients. The results from these studies are as follows:

A long-term, open-label safety study of 164 CKD Stage 5 patients (mean dose of 7.5 mcg three times per week), demonstrated that mean serum Ca, P, and Ca × P remained within clinically appropriate ranges with PTH reduction (mean decrease of 319 pg/mL at 13 months).

Medication Guide

PATIENT INFORMATION

The patient should be instructed that, to ensure effectiveness of Zemplar therapy, it is important to adhere to a dietary regimen of calcium supplementation and phosphorus restriction. Appropriate types of phosphate-binding compounds may be needed to control serum phosphorus levels in patients with chronic kidney disease (CKD) Stage 5, but excessive use of aluminum containing compounds should be avoided (see WARNINGS). Patients should also be carefully informed about the symptoms of elevated calcium (see WARNINGS).

Medication Guide

PATIENT INFORMATION

The patient should be instructed that, to ensure effectiveness of Zemplar therapy, it is important to adhere to a dietary regimen of calcium supplementation and phosphorus restriction. Appropriate types of phosphate-binding compounds may be needed to control serum phosphorus levels in patients with chronic kidney disease (CKD) Stage 5, but excessive use of aluminum containing compounds should be avoided (see WARNINGS). Patients should also be carefully informed about the symptoms of elevated calcium (see WARNINGS).