英文药名: Zenapax(Daclizumab)

中文药名: 赛尼哌注射液，达利珠单抗

品牌药生产厂家: Roche Pharmaceuticals

药品介绍

赛尼哌注射液, Zenapax
成分: 抗Tac单抗 Daclizumab
药物分类: 免疫抑制剂

适应症：
适用于预防肾移植后急性排斥反应的发生，可与包含环孢素和皮质类固醇激素的免疫抑制方案一起使用。

特性：
每瓶注射液内含25 mg 达利珠单抗(5 mg/ml)，并含有以下赋形剂：聚山梨醇脂80，氯化钠，磷酸二氢钠，磷酸氢二钠，盐酸，氢氧化钠和注射用水。为澄清或淡乳白色液体。

用法用量：
推荐剂量为1 mg/kg，加入0.9％生理盐水50 ml中，由周围或中央静脉输入15分钟以上。本药首剂应在移植前24小时内给药，以后每隔14天给药1次，5次为一疗程。每次给药必须在预定给药时间的前后一天内进行。严重肾损害的病人不必进行剂量调整。

禁忌： 已知对达利珠单抗或此产品的任何成分具有高敏感性的病人禁止使用。
规格：25mg/5ml

×赛尼哌是器官移植领域第一个人源化的单克隆抗体，可以特异性地抑制T淋巴细胞介导的免疫反应，是近年来使用的一种新型免疫抑制剂。在国外多中心的临床研究中发现它可以有效地抑制器官移植后的急性排斥反应，明显提高移植物的1年存活率，而且有良好的耐受性。

×药理作用　　
赛尼哌含有的达利珠单抗是一种重组并人源化的IgG1（G亚型免疫球蛋白）抗TAC抗体，其含90%人IgG序列和10%的鼠序列。其功能类似于白介素-2（IL-2）受体拮抗剂，与IL-2受体复合物（在激活的T细胞表面表达）的a-亚单位或TAC亚单位高特异性结合，从而抑制IL-2介导的淋巴细胞激活，也就是抑制了排斥反应过程中细胞免疫的关键通道。但是，赛尼哌发挥免疫抑制作用的确切机制还不完全清楚。该药发挥免疫抑制的主要机制是依赖IL-2的饱和程度和竞争性抑制IL-2依赖的T细胞增生，在体外抗体依赖细胞介导的细胞毒作用可引起抗Tac单抗作用的T细胞溶解，这可能是该药免疫抑制的另一种机制。间接的免疫调理机制如IL-2表达水平下调，选择性地灭活和破坏抗原刺激Tac结合的淋巴细胞，与激活T细胞表面的Fc段和Fc受体相互作用。也有些学者认为，赛尼哌能通过抑制由IL-2诱导的β、γ链的联合以及其进一步的磷酸化，而直接于受体水平影响IL-2的信号传递。

××T淋巴细胞表面IL-2受体 　　
T淋巴细胞表面IL-2受体由α（p55）、β（p75）、γ（p64）三个亚单位组成，在大多数T、B和NK细胞表面有IL-2受体β和γ两个亚单位，而α亚单位（又称Tac或CD25）仅表达于激活T淋巴细胞表面。

××与IL-2受体结合 　　
赛尼哌的蛋白质的结构保留了对Tac的高亲和性。对在人T细胞链（HuT-102）表达的Tac亲和常数（ka）为3×10-9mol/L。肾移植患者在接受赛尼哌治疗时（术前24h内给药1mg/kg，术后每两周一次，共5次），循环中淋巴细胞与IL-2结合的峰值为84%，最后一次给药后4周为74%。循环中淋巴细胞表达IL-2的饱和度超过95%。赛尼哌治疗组应用外源性抗CD25抗体沾染的T细胞数，明显低于安慰组，在移植后10h内（2%比15%阳性染色细胞）直到移植后4个月（最后一次用药后2个月，分别为3%比28%阳性染色细胞）均是如此。移植后6个月，循环淋巴细胞上自由IL-2数恢复到术前水平，分别为29%比21%阳性染色细胞。当移植前13h给予赛尼哌1mg/kg，可使小儿实质性淋巴组织中T淋巴细胞和外周血淋巴细胞IL-2达到饱和。赛尼哌阻断IL-2与激活T淋巴细胞表面IL-2R的结合，阻断IL-2介导的Jak-1、Jak-3和Stat5的激活，阻断细胞由GO期进入G1期。

××移植T细胞增生 　　
在体外研究中，通过测定胸苷结合率可显示，赛尼哌具有抑制IL-2诱导由破伤风类毒素抗原激活的T细胞的增生。赛尼哌表现出最大活性类似于鼠抗Tac抗体，抑制50%T细胞增生需要是平均浓度为0.5-1mg/L。体外研究表明，当赛尼哌与人Mikβ1抗体（HuMikβ1，特异性作用于IL-2R和IL-15Rβ亚单位）联合应用时，能增强抑制由IL-2诱导的活性T细胞的增生。赛尼哌（2mg/L）加HuMikβ1（5mg/L）达到抑制50%T细胞增生时所需的浓度，比单用赛尼哌时（20mg/L）低。

××抗体依赖性细胞介导的细胞毒作用 　　
与鼠抗体不同，在体外赛尼哌可以介导抗体依赖细胞介导的细胞毒作用来对抗人单核细胞，而且当效应器细胞上IL-2R表达增加时，这种抑制活性也将增加。赛尼哌可使循环T细胞上IL-2表达下调，在一组研究中肾移植患者，发现赛尼哌治疗组淋巴细胞上总IL-2表达，在整个治疗过程中比安慰组低。

××赛尼哌不影响总淋巴细胞计数 　　
在肾移植后14天和56天，赛尼哌治疗组与安慰组患者淋巴细胞计数相仿（56天后为0.9对1.1×103/ul）。同样一期和二期临床研究发现，接受赛尼哌治疗的患者总T细胞数、辅助/诱导T细胞数、细胞毒/抑制性T细胞数、自然杀伤细胞数或B细胞数几乎没有变化。

××免疫原性 　　
免疫原性低,研究中未发现具有临床意义的抗体。

×药代动力学　　
赛尼哌的血清浓度是通过一种特异性"受体依赖"ELISA法来测定的。在肾移植受者中获得的关于静脉注射赛尼哌时药代动力学的有限资料提示：赛尼哌1mg/kg，每两周一次，共5个剂量（超过8周），可保持有效的血清药物浓度直到移植后12周（急性排斥反应的易发期），该浓度能有效饱和IL-2R，抑制T细胞增生，平均血清药物浓度峰值（平均值±标准差）从首剂后的21±14mg/L增加到第5次给药后的32±22mg/L，第5次给药前的平均谷值浓度是7.6±4.0mg/L。赛尼哌的分布容积很小（约5.3L），提示渗透到血管外空间的量很小。在大型人群的药代动力学分析中使用了一个2室开放模型，测算出一个典型80kg，45岁高加索男性赛尼哌全身清除率为15.1ml/h。赛尼哌的全身清除率存在大约20%的个体差异，而且主要与体重相关。全身清除率还受年龄、性别和种族的影响，但影响较小。在一个小型的一/二期临床研究中（n=12），体重为40-120kg不等的患者，赛尼哌全身清除率在9-15ml/h之间，单次和多次给药后清除率相仿。在同种异体肾移植受者中，赛尼哌清除半衰期较长，平均大约480（270-919）h，与人类IgG相似。尚不知道赛尼哌治疗是否会通过胎盘屏障或被分泌到人乳中损伤胎儿。

×药物相互作用和配伍禁忌　　
在临床实验中赛尼哌与下列用于移植的药物合用，不会增加不良反应的发生：环孢素、霉酚酸酯、更昔洛韦、阿昔洛韦、他克莫司、硫唑嘌呤、和皮质类固醇激素。赛尼哌和聚氯乙烯、聚氯烯袋或灌注装置间未发现配伍禁忌。

×临床疗效
××急性排斥反应 　　
在三期临床中，赛尼哌加环孢素为主的二联和三联免疫抑制治疗方案与安慰剂组相比，明显降低移植肾急性排斥反应的发生率，I年内急性排斥反应的发生率分别为28%，43%，p=0.001。在两个肾移植中心的研究中发现：第6个月时，赛尼哌治疗组与安慰组的急性排斥反应的发生率分别是28%对47%（p=0.001）和22%对35%（p=0.03）。赛尼哌可以明显降低每例患者急性排斥反应的次数，且比安慰剂组明显延迟首次急性排斥反应发生的时间。在Vincenti等研究中，赛尼哌组首次急性排斥反应发生时间的中位数为73天，安慰剂组为30天。 Ｋ.Leitz等用赛尼哌与他克莫司、霉酚酸酯和皮质类固醇激素对219例首次肾移植患者随访11个月，活检证实的急排仅为3.2%。　　
D.B.Kaufman等对175例胰肾联合移植患者随访6个月，赛尼哌组活检证实的急排的平均时间为19.5天，而对照组为17天，且赛尼哌组急性排斥的严重程度（Banff分级）比对照组低。赛尼哌组平均血清肌酐浓度为1.2mg%，对照组为1.35 mg%，（p=0.08）。T.G.Heffron等对54例肝移植患者随访19个月，赛尼哌组的急性排斥反应的发生率较对照组低（14.8%vs31.9%,p=0.03）。Ｋ.Leitz等用赛尼哌对50例具有高危免疫学因素的心脏移植患者进行免疫抑制诱导治疗结合良好的HLA分型，有效地预防了急性排斥反应的发生。
**移植物和患者存活率 　　
在赛尼哌的三期临床研究中，两个移植中心的赛尼哌组比安慰剂组的移植肾和患者存活率都高,分别是88%和95%对83%和90%，但无统计学差异。赛尼哌组移植后1年移植肾失功能发生率为8.6%，安慰剂组为13.4%。在Nashan等的研究中，1年患者存活率分别为99%对94%，p=0.01。 Henrik Ekberg等对535例首次尸体肾移植患者进行随访，赛尼哌组一年移植物存活率为91.4，安慰剂组为86.6，p=0.065；患者存活率为98.5%，安慰剂组为95.1%，p=0.022。　　
B.H.Markus等对36例术后使用赛尼哌和他克莫司的肝移植患者随访两年后发现：赛尼哌诱导治疗安全、有效，并且可以降低他克莫司和皮质类固醇激素的用量。

**肾移植高危患者的应用 　　
非洲-美洲肾移植受者和西班牙肾移植受者较其他人群发生急性排斥的比率高。Meier-Kriesche等对105例上述肾移植高危患者进行研究，结果赛尼哌组急性排斥的发生率明显低于对照组，分别为26.4%和49.3%，而且对照组有8例出现多次排斥，赛尼哌组则无一例发生。

**移植肾功能延迟恢复患者的应用 　　
在赛尼哌的三期临床研究中，两个移植中心的赛尼哌组和安慰剂组移植肾功能延迟恢复的发生率的差异并不显著,分别为40%比38%和21%比29%。然而这些研究表明在移植后6个月时，赛尼哌组移植肾功能比安慰剂组好：SCr150.28对167.96umol/L，肾小球滤过率为58比51ml/min（p=0.02）。Chang George等使用赛尼哌、霉酚酸酯和Sirolimus治疗14例移植肾功能延迟恢复患者，收到满意的免疫抑制效果。但是，Vincenti等研究中两组移植肾功能无显著差异。

**两剂赛尼哌的临床效果 　　
赛尼哌的标准用法是首剂于移植前24小时内给药，以后每次给药间隔14天，五剂为一个疗程。　　M.H.Deierhoi 等应用两剂方案，于移植当天使用首剂赛尼哌，出院当天使用第二剂治疗，同样明显的降低了尸体肾移植患者的急排率和在住院率。R.R.Alloway等对180例胰肾联合移植患者进行研究，结果发现两剂赛尼哌组和五剂赛尼哌组预防胰肾联合移植后急排的疗效相仿，而且两剂赛尼哌组患者中无排异或移植物失功能的患者比例较高。Eckhoff 等对137例肝移植患者的研究中发现，两剂赛尼哌组和五剂赛尼哌组预防肝移植后急排的疗效相仿。

**赛尼哌的耐受性 　　
在三期临床研究中发现，赛尼哌并不增加副作用的发生率。赛尼哌组与安慰剂组治疗中所有可能与治疗有关的副作用发生率无显著差异。

ZENAPAX - daclizumab injection, solution, concentrate 
Hoffmann-La Roche Inc

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ZENAPAX®
(daclizumab)
STERILE CONCENTRATE FOR INJECTION

WARNING Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe ZENAPAX® (daclizumab). The physician responsible for ZENAPAX administration should have complete information requisite for the follow-up of the patient. ZENAPAX should only be administered by healthcare personnel trained in the administration of the drug who have available adequate laboratory and supportive medical resources.

DESCRIPTION

ZENAPAX® (daclizumab) is an immunosuppressive, humanized IgG1 monoclonal antibody produced by recombinant DNA technology that binds specifically to the alpha subunit (p55 alpha, CD25, or Tac subunit) of the human high-affinity interleukin-2 (IL-2) receptor that is expressed on the surface of activated lymphocytes.

Daclizumab is a composite of human (90%) and murine (10%) antibody sequences. The human sequences were derived from the constant domains of human IgG1 and the variable framework regions of the Eu myeloma antibody. The murine sequences were derived from the complementarity-determining regions of a murine anti-Tac antibody. The molecular weight predicted from the DNA sequence is 144 kilodaltons.

ZENAPAX 25 mg/5 mL is supplied as a clear, sterile, colorless concentrate for further dilution and intravenous administration. Each milliliter of ZENAPAX contains 5 mg of daclizumab and 3.6 mg sodium phosphate monobasic monohydrate, 11 mg sodium phosphate dibasic heptahydrate, 4.6 mg sodium chloride, 0.2 mg polysorbate 80, and may contain hydrochloric acid or sodium hydroxide to adjust the pH to 6.9. No preservatives are added.

CLINICAL PHARMACOLOGY

General

Mechanism of Action

Daclizumab functions as an IL-2 receptor antagonist that binds with high-affinity to the Tac subunit of the high-affinity IL-2 receptor complex and inhibits IL-2 binding. Daclizumab binding is highly specific for Tac, which is expressed on activated but not resting lymphocytes. Administration of ZENAPAX inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection.

While in the circulation, ZENAPAX impairs the response of the immune system to antigenic challenges. Whether the ability to respond to repeated or ongoing challenges with those antigens returns to normal after ZENAPAX is cleared is unknown (see PRECAUTIONS).

Pharmacokinetics

Adults

In clinical trials involving renal allograft patients treated with a 1 mg/kg IV dose of ZENAPAX every 14 days for a total of five doses, peak serum concentration (mean ± SD) rose between the first dose (21 ± 14 µg/mL) and fifth dose (32 ± 22 µg/mL). The mean trough serum concentration before the fifth dose was 7.6 ± 4.0 µg/mL. Population pharmacokinetic analysis of the data using a two-compartment open model gave the following values for a reference patient (45-year-old male Caucasian patient with a body weight of 80 kg and no proteinuria): systemic clearance = 15 mL/hour, volume of central compartment = 2.5 liter, volume of peripheral compartment = 3.4 liter. The estimated terminal elimination half-life for the reference patient was 20 days (480 hours), which is similar to the terminal elimination half-life for human IgG (18 to 23 days). Bayesian estimates of terminal elimination half-life ranged from 11 to 38 days for the 123 patients included in the population analysis. The influence of body weight on systemic clearance supports the dosing of ZENAPAX on a milligram per kilogram (mg/kg) basis. For patients studied, this dosing maintained drug exposure within 30% of the reference exposure. Covariate analyses showed that no dosage adjustments based on age, race, gender or degree of proteinuria, are required for renal allograft patients. The estimated interpatient variability (percent coefficient of variation) in systemic clearance and central volume of distribution were 15% and 27%, respectively.

Pediatrics

Pharmacokinetic parameters were evaluated in 61 pediatric patients treated with a 1 mg/kg IV dose of ZENAPAX every 14 days for a total of five doses. Peak serum concentration (mean ± SD) rose between the first dose (16 ± 12 µg/mL) and fifth dose (21 ± 14 µg/mL). The mean trough serum concentration before the fifth dose was 5.0 ± 2.7 µg/mL. Population pharmacokinetic analysis of the data using a two-compartment open model gave the following values for a reference patient (Caucasian patient with a body weight of 29.7 kg): systemic clearance = 10 mL/hour, volume of central compartment = 2.0 liter, volume of peripheral compartment = 1.4 liter. The estimated terminal elimination half-life for the reference patient was 13 days (317 hours). For the patients studied, this dosing maintained drug exposure within 50% of the reference exposure. Covariate analyses suggested that disposition parameters were not influenced to a clinically relevant extent by race, gender or degree of proteinuria. The estimated interpatient variability (percent coefficient of variation) in systemic clearance and central volume of distribution were 30% and 40%, respectively.

Pharmacodynamics

In vitro and in vivo data suggest that serum levels of 5 to 10 µg/mL are necessary for saturation of the Tac subunit of the IL-2 receptors to block the responses of activated T lymphocytes. At the recommended dosage regimen, daclizumab saturates the Tac subunit of the IL-2 receptor for approximately 90 and 120 days posttransplant, respectively in pediatric and adult patients. The duration of clinically significant IL-2 receptor blockade after the recommended course of ZENAPAX is not known. No significant changes to circulating lymphocyte numbers or cell phenotypes were observed by flow cytometry. Cytokine release syndrome has not been observed after ZENAPAX administration.

CLINICAL STUDIES

The safety and efficacy of ZENAPAX for the prophylaxis of acute organ rejection in adult patients receiving their first cadaveric kidney transplant were assessed in two randomized, double-blind, placebo-controlled, multicenter trials. These trials compared a dose of 1.0 mg/kg of ZENAPAX with placebo when each was administered as part of standard immunosuppressive regimens containing either cyclosporine and corticosteroids (double-therapy trial, no US sites) or cyclosporine, corticosteroids, and azathioprine (triple-therapy trial, predominantly US sites) to prevent acute renal allograft rejection. ZENAPAX dosing was initiated within 24 hours pretransplant, with subsequent doses given every 14 days for a total of five doses.

The primary efficacy endpoint of both trials was the proportion of patients who developed a biopsy-proven acute rejection episode within the first 6 months following transplantation. As shown in Table 1, this incidence was significantly lower in the group treated with ZENAPAX in both the double-therapy and triple-therapy trials.

Treatment with ZENAPAX was associated with better patient survival up to 3 years posttransplant in the double-therapy study. No difference in patient survival was observed in the triple-therapy study between patients treated with ZENAPAX or placebo up to 3 years posttransplant. No difference was observed for graft survival between treatment groups in both studies at 3 years posttransplant.

The incidence of delayed graft function was not different between patients treated with placebo or ZENAPAX in either study. No difference in graft function was observed 1 year and 3 years posttransplant in either study between patients treated with placebo or ZENAPAX.

In a randomized, double-blind study to assess tolerability, pharmacokinetics, and drug interactions in renal allograft recipients, ZENAPAX (50 patients) or placebo (25 patients) was added to an immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and corticosteroids. In this study, the addition of ZENAPAX did not result in an increased incidence of adverse events or a change in the types of adverse events reported. The incidence of the combined endpoint of biopsy-proven or clinically presumptive acute rejection was 20% (5 of 25 patients) in the placebo group and 12% (6 of 50 patients) in the ZENAPAX group. Although numerically lower, the difference in acute rejection was not significant. However, in a randomized, double-blind, placebo-controlled trial of ZENAPAX in cardiac transplant recipients (n=434) receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality was increased in patients randomized to receive ZENAPAX compared with those randomized to receive placebo (see WARNINGS and ADVERSE REACTIONS).

INDICATIONS AND USAGE

ZENAPAX is indicated for the prophylaxis of acute organ rejection in patients receiving renal transplants. It is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids.

The efficacy of ZENAPAX for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated.

CONTRAINDICATION

ZENAPAX is contraindicated in patients with known hypersensitivity to daclizumab or to any components of this product.

WARNINGS (see Boxed WARNING)

The use of ZENAPAX as part of an immunosuppressive regimen including cyclosporine, mycophenolate mofetil, and corticosteroids may be associated with an increase in mortality. In a randomized, double-blind, placebo-controlled trial of ZENAPAX for the prevention of allograft rejection in 434 cardiac transplant recipients receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving ZENAPAX compared to those receiving placebo (7% vs 5%, respectively at 6 months; 10% vs 6% respectively at 12 months). Some, but not all, of the increase in mortality appeared related to a higher incidence of severe infections. Concomitant use of anti-lymphocyte antibody therapy may also be a factor in some of the fatal infections.

ZENAPAX should be administered under qualified medical supervision. Patients should be informed of the potential benefits of therapy and the risks associated with administration of immunosuppressive therapy.

While the incidence of lymphoproliferative disorders and opportunistic infections in the limited clinical trial experience was no higher in patients treated with ZENAPAX compared with placebo-treated patients, patients on immunosuppressive therapy are at increased risk for developing lymphoproliferative disorders and opportunistic infections and should be monitored accordingly.

Hypersensitivity

Severe, acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to ZENAPAX and following re-exposure. These reactions may include hypotension, bronchospasm, wheezing, laryngeal edema, pulmonary edema, cyanosis, hypoxia, respiratory arrest, cardiac arrhythmia, cardiac arrest, peripheral edema, loss of consciousness, fever, rash, urticaria, diaphoresis, pruritus, and/or injection site reactions. If a severe hypersensitivity reaction occurs, therapy with ZENAPAX should be permanently discontinued. Medications for the treatment of severe hypersensitivity reactions including anaphylaxis should be available for immediate use. Patients previously administered ZENAPAX should only be re-exposed to a subsequent course of therapy with caution. The potential risks of such re-administration, specifically those associated with immunosuppression, are not known.

PRECAUTIONS

General

It is not known whether ZENAPAX use will have a long-term effect on the ability of the immune system to respond to antigens first encountered during ZENAPAX-induced immunosuppression.

Re-administration of ZENAPAX after an initial course of therapy has not been studied in humans. The potential risks of such re-administration, specifically those associated with immunosuppression and/or the occurrence of anaphylaxis/anaphylactoid reactions, are not known.

Drug Interactions

The following medications have been administered with ZENAPAX in clinical trials in renal allograft patients with no incremental increase in adverse reactions: cyclosporine, mycophenolate mofetil, ganciclovir, acyclovir, azathioprine, and corticosteroids. Very limited experience exists in these patients with the use of ZENAPAX concomitantly with tacrolimus, muromonab-CD3, antithymocyte globulin, and anti-lymphocyte globulin.

In renal allograft recipients (n=50) treated with ZENAPAX and mycophenolate mofetil, no pharmacokinetic interaction between ZENAPAX and mycophenolic acid, the active metabolite of mycophenolate mofetil, was observed.

However, in a large clinical study in cardiac transplant recipients (n=434), the use of ZENAPAX as part of an immunosuppression regimen including cyclosporine, mycophenolate mofetil, and corticosteroids was associated with an increase in mortality, particularly in patients receiving concomitant anti-lymphocyte antibody therapy and in patients who developed severe infections (see WARNINGS and ADVERSE REACTIONS: Incidence of Infectious Episodes).

Carcinogenesis, Mutagenesis and Impairment of Fertility

Long-term studies to evaluate the carcinogenic potential of ZENAPAX have not been performed. ZENAPAX was not genotoxic in the Ames or the V79 chromosomal aberration assays, with or without metabolic activation. The effect of ZENAPAX on fertility is not known, because animal reproduction studies have not been conducted with ZENAPAX (see WARNINGS and ADVERSE REACTIONS).

Pregnancy

Pregnancy Category C: A preclinical developmental toxicity study with ZENAPAX has shown an increased risk of early prenatal loss in cynomolgus monkeys compared to placebo. However, the clinical experience of ZENAPAX exposed pregnancies is still limited. In general, IgG molecules are known to cross the placental barrier. ZENAPAX should not be used in pregnant women unless the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should use effective contraception before beginning ZENAPAX therapy, during therapy, and for 4 months after completion of ZENAPAX therapy.

Nursing Mothers

It is not known whether ZENAPAX is excreted in human milk. However, in preclinical developmental toxicity studies with ZENAPAX, four out of seven lactating cynomolgus monkeys given a 5-10 fold multiple (10mg/kg) of the normal human dose were found to secrete very low levels of ZENAPAX (0.17 – 0.28% of maternal serum levels) in breast milk. Because many drugs are excreted in human milk, including human antibodies, and because of the potential for adverse reactions, a decision should be made 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 ZENAPAX have been established in pediatric patients from 11 months to 17 years of age. Use of ZENAPAX in this age group is supported by evidence from adequate and well-controlled studies of ZENAPAX in adults with additional pediatric pharmacokinetic data (see CLINICAL PHARMACOLOGY). Data from the pediatric pharmacokinetic study were also analyzed for efficacy, immunogenicity and safety. In an open-label study, 60 pediatric renal transplant recipients [median age of 10 years] received standard immunosuppressive agents in addition to a regimen of ZENAPAX administered at a dose of 1.0 mg/kg at intervals of 14 days for a total of 5 doses, starting immediately before transplantation. In this study, the combined incidence of biopsy-proven and clinically presumptive acute rejection at 1 year posttransplant was 17% (10/60). Patient and graft survival at 1 year posttransplant were 100% and 96.7%, respectively. The incidence of anti-daclizumab antibodies (34%) observed in the first 3 months posttransplant was higher than the incidence previously observed in adult patients (14%) (see ADVERSE REACTIONS: Immunogenicity).

The safety profile of ZENAPAX in pediatric transplant patients was shown to be comparable with that in adult transplant patients with the exception of the following adverse events, which occurred more frequently in pediatric patients (>15% difference in incidence): diarrhea, post-operative pain, fever, vomiting, aggravated hypertension, pruritus, and infections of the upper respiratory tract and urinary tract.

It is not known whether the immune response to vaccines, infection, and other antigenic stimuli administered or encountered during ZENAPAX therapy is impaired or whether such response will remain impaired after ZENAPAX therapy.

Also see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.

Geriatric Use

Clinical studies of ZENAPAX did not include sufficient numbers of subjects age 65 and older to determine whether they respond differently from younger subjects. Caution must be used in giving immunosuppressive drugs to elderly patients.

ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug. Rates observed in clinical studies may not reflect those observed in clinical practice. Adverse reaction information obtained in clinical trials does, however, provide a basis for identifying adverse events that appear to be related to drug use and for approximating the rate of occurrence.

The safety of ZENAPAX was determined in four clinical studies of renal allograft rejection, three of which were randomized controlled clinical trials, in 629 patients receiving renal allografts of whom 336 received ZENAPAX and 293 received placebo. All patients received concomitant cyclosporine and corticosteroids. In these clinical trials, ZENAPAX did not appear to alter the pattern, frequency or severity of known major toxicities associated with the use of immunosuppressive drugs.

The use of ZENAPAX was associated with a higher incidence of mortality when compared to placebo in a large (n=434) randomized controlled study of patients receiving cardiac transplants (see WARNINGS and Incidence of Infectious Episodes).

Adverse events were reported by 95% of the patients in the placebo-treated group and 96% of the patients in the group treated with ZENAPAX. The proportion of patients prematurely withdrawn from the combined studies because of adverse events was 8.5% in the placebo-treated group and 8.6% in the group treated with ZENAPAX.

ZENAPAX did not increase the number of serious adverse events observed compared with placebo. The most frequently reported adverse events were gastrointestinal disorders, which were reported with equal frequency in ZENAPAX- (67%) and placebo-treated (68%) patient groups.

The incidence and types of adverse events were similar in both placebo-treated patients and patients treated with ZENAPAX. The following adverse events occurred in ≥5% of patients treated with ZENAPAX. These events included: Gastrointestinal System: constipation, nausea, diarrhea, vomiting, abdominal pain, pyrosis, dyspepsia, abdominal distention, epigastric pain not food-related; Metabolic and Nutritional: edema extremities, edema; Central and Peripheral Nervous System: tremor, headache, dizziness; Urinary System: oliguria, dysuria, renal tubular necrosis; Body as a Whole - General: posttraumatic pain, chest pain, fever, pain, fatigue; Autonomic Nervous System: hypertension, hypotension, aggravated hypertension; Respiratory System: dyspnea, pulmonary edema, coughing; Skin and Appendages: impaired wound healing without infection, acne; Psychiatric: insomnia; Musculoskeletal System: musculoskeletal pain, back pain; Heart Rate and Rhythm: tachycardia; Vascular Extracardiac: thrombosis; Platelet, Bleeding and Clotting Disorders: bleeding; Hemic and Lymphatic: lymphocele.

The following adverse events occurred in <5% and ≥2% of patients treated with ZENAPAX. These included: Gastrointestinal System: flatulence, gastritis, hemorrhoids; Metabolic and Nutritional: fluid overload, diabetes mellitus, dehydration; Urinary System: renal damage, hydronephrosis, urinary tract bleeding, urinary tract disorder, renal insufficiency; Body as a Whole - General: shivering, generalized weakness; Central and Peripheral Nervous System: urinary retention, leg cramps, prickly sensation; Respiratory System: atelectasis, congestion, pharyngitis, rhinitis, hypoxia, rales, abnormal breath sounds, pleural effusion; Skin and Appendages: pruritus, hirsutism, rash, night sweats, increased sweating; Psychiatric: depression, anxiety; Musculoskeletal System: arthralgia, myalgia; Vision: vision blurred; Application Site: application site reaction.

Incidence of Malignancies

One and 3 years posttransplant, the incidence of malignancies was 2.7% and 7.8%, respectively, in the placebo group compared with 1.5% and 6.4%, respectively, in the ZENAPAX group. Addition of ZENAPAX did not increase the number of posttransplant lymphomas up to 3 years posttransplant. Lymphomas occurred at a frequency of ≤1.5% in both placebo-treated and ZENAPAX-treated groups.

Hyperglycemia

No differences in abnormal hematologic or chemical laboratory test results were seen between groups treated with placebo or ZENAPAX with the exception of fasting blood glucose. Fasting blood glucose was measured in a small number of patients treated with placebo or ZENAPAX. A total of 16% (10 of 64 patients) of placebo-treated and 32% (28 of 88 patients) of patients treated with ZENAPAX had high fasting blood glucose values. Most of these high values occurred either on the first day posttransplant when patients received high doses of corticosteroids or in patients with diabetes.

Incidence of Infectious Episodes

The overall incidence of infectious episodes, including viral infections, fungal infections, bacteremia and septicemia, and pneumonia, was not higher in patients treated with ZENAPAX than in placebo-treated patients in trials of renal transplantation. In a large randomized study of ZENAPAX used for the prevention of allograft rejection in patients receiving cardiac allografts, more patients receiving ZENAPAX experienced severe or fatal infections after 12 months of therapy when compared to those receiving placebo (10% vs 7%, respectively). The risks of infection or death may be increased in patients receiving concomitant anti-lymphocyte antibody therapy (see WARNINGS).

The types of infections reported in trials of renal transplantation were similar in both the ZENAPAX-treated and the placebo-treated groups. Cytomegalovirus infection was reported in 16% of the patients in the placebo group and 13% of the patients in the ZENAPAX group. One exception was cellulitis and wound infections, which occurred in 4.1% of placebo-treated patients and 8.4% of patients treated with ZENAPAX. At 1 year posttransplant, 7 placebo patients and 1 patient treated with ZENAPAX had died of an infection. At 3 years posttransplant, 8 placebo patients and 4 patients treated with ZENAPAX had died of infection.

Immunogenicity

Low titers of anti-idiotype antibodies to daclizumab were detected in the adult patients treated with ZENAPAX with an overall incidence of 14%. The incidence of anti-daclizumab antibodies observed in the pediatric patients was 34%. No antibodies that affected efficacy, safety, serum daclizumab levels or any other clinically relevant parameter examined were detected. The data reflect the percentage of patients whose test results were considered positive for antibodies to daclizumab in an ELISA assay and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to daclizumab with the incidence of antibodies to other products may be misleading.

Post-Marketing Experience

The following adverse reactions have been identified and reported during post-approval use of ZENAPAX (daclizumab). Because the reports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.

Severe acute hypersensitivity reactions including anaphylaxis characterized by hypotension, bronchospasm, wheezing, laryngeal edema, pulmonary edema, cyanosis, hypoxia, respiratory arrest, cardiac arrhythmia, cardiac arrest, peripheral edema, loss of consciousness, fever, rash, urticaria, diaphoresis, pruritus, and/or injection site reactions, as well as cytokine release syndrome, have been reported during post-marketing experience with ZENAPAX. The relationship between these reactions and the development of antibodies to ZENAPAX is unknown.

OVERDOSAGE

There have not been any reports of overdoses with ZENAPAX. A maximum tolerated dose has not been determined in patients. A dose of 1.5 mg/kg has been administered to bone marrow transplant recipients without any associated adverse events.

DOSAGE AND ADMINISTRATION

ZENAPAX is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. The recommended dose for ZENAPAX in adult and pediatric patients is 1.0 mg/kg (see PRECAUTIONS: Pediatric Use). The calculated volume of ZENAPAX should be mixed with 50 mL of sterile 0.9% sodium chloride solution and administered via a peripheral or central vein over a 15-minute period.

Based on the clinical trials, the standard course of ZENAPAX therapy is five doses. The first dose should be given no more than 24 hours before transplantation. The four remaining doses should be given at intervals of 14 days.

No dosage adjustment is necessary for patients with severe renal impairment. No dosage adjustments based on other identified covariates (age, gender, proteinuria, race) are required for renal allograft patients. No data are available for administration in patients with severe hepatic impairment.

Instructions for Administration

• ZENAPAX IS NOT FOR DIRECT INJECTION. The calculated volume should be diluted in 50 mL of sterile 0.9% sodium chloride solution before intravenous administration to patients. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE.
• Parenteral drug products should be inspected visually for particulate matter and discoloration before administration. If particulate matter is present or the solution colored, do not use.
• Care must be taken to assure sterility of the prepared solution, since the drug product does not contain any antimicrobial preservative or bacteriostatic agents.
• ZENAPAX is a colorless solution provided as a single-use vial; any unused portion of the drug should be discarded.
• Once the infusion is prepared, it should be administered intravenously within 4 hours. If it must be held longer, it should be refrigerated between 2° to 8°C (36° to 46°F) for up to 24 hours. After 24 hours, the prepared solution should be discarded.
• No incompatibility between ZENAPAX and polyvinyl chloride or polyethylene bags or infusion sets has been observed. No data are available concerning the incompatibility of ZENAPAX with other drug substances. Other drug substances should not be added or infused simultaneously through the same intravenous line.
• ZENAPAX should only be administered by healthcare personnel trained in the administration of the drug who have available adequate laboratory and supportive medical resources.

HOW SUPPLIED

ZENAPAX is supplied in single-use glass vials. Each vial contains 25 mg of daclizumab in 5 mL of solution (NDC 0004-0501-09). Vials should be stored between the temperatures of 2° to 8°C (36° to 46°F); do not shake or freeze. Protect undiluted solution against direct light. Diluted medication is stable for 24 hours at 4°C or for 4 hours at room temperature.

Roche Pharmaceuticals

Hoffmann-La Roche Inc.

340 Kingsland Street

Nutley, NJ 07110–1199

US Govt. Lic. No. 0136

3609650 USA
27899043

Revised: September 2005

Copyright © 1999-2005 by Hoffmann-La Roche Inc. All rights reserved.
 
Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

PRINCIPAL DISPLAY PANEL - 25 mg/5 mL Vial Label

NDC 0004-0501-09

Zenapax®
(daclizumab)

Sterile
Concentrate for
Injection

25 mg/5 mL
(5 mg/mL)

Rx only
1 Vial
(5 mL Size)