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目前,美国FDA批准了CSL Behring公司开发的来自人血浆的20%人免疫球蛋白(human immunoglobulin)皮下输注液Hizentra,用于治疗已被确诊的原发性免疫缺陷患者。作为一种一周1次用免疫球蛋白替代治疗药物,Hizentra能经将体内免疫球蛋白维持在正常且稳定水平而提供对感染的有效预防作用。原发性免疫缺陷是一组(有近100种亚型)通常由遗传因素引起的疾病,会使免疫系统发生功能障碍,导致患者处在极高的病菌感染和反复感染的风险之中。Hizentra是FDA至今批准的第一种皮下输注用免疫球蛋白制剂,同时也是FDA迄今批准的浓度最高的一种免疫球蛋白制剂。
Hizentra，免疫球蛋白皮下(人)，20%液体是备用，消毒20%(0.2 g/mL)蛋白液体多价人免疫球蛋白G(IgG)为皮下给予的制备物。Hizentra是从大量合并人血浆通过低温乙醇分馏, 辛酸分馏,和阴离子交换层析的结合制造。IgG蛋白不会受热或化学或酶修饰。保留IgG分子的Fc和Fab功能。Fab功能测试包括抗原结合的能力，和Fc功能测试，包括补体活化和Fc-受体介导的白细胞活化(用符合IgG测定)。
Hizentra有纯度98%的IgG和pH 4.6至5.2。Hizentra含接近250(范围：210至290 mmol/L)L-脯氨酸(一种非必需氨基酸)作为一种稳定剂，10至30 mg/L聚山梨醇酯80，和痕量钠。Hizentra含≤50 μg/mL IgA. Hizentra不含no 碳水化合物稳定剂(如，蔗糖，麦芽糖)和无防腐剂。
适应证和用途：
Hizentra是一种免疫球蛋白皮下(人)(IGSC)，20%液体适用于治疗原发性免疫缺陷症。
剂量和给药方法：
只为皮下输注。不要注入血管内。
在患者末次免疫球蛋白(人) (IGIV)静脉输注后，开始用Hizentra治疗。
剂量
1. Hizentra的初始每周剂量是计算达到全身血清IgG暴露(浓度时间曲线下面积[AUC])不低于既往IGIV 治疗。
初始剂量 =[1.53 × 既往IGIV剂量(克)]/ IGIV给予间周数
转换剂量克至毫升(mL)，计算剂量(克)乘5。
2. 基于临床反应和血清IgG低谷水平调整给予时间。在用Hizentra治疗后2至3个月测定血清IgG低谷水平。调整剂量以达到血清IgG低谷水平为末次IGIV治疗低谷水平的1.3倍。
给药方法
1. 输注部位–腹部、大腿、上臂和/或侧臀部。同时用至4个注射部位，部位间至少2英寸。
2. 输注容积–首次输注，至15 mL每注射部位，第4次输注后可增至20 mL每注射部位和最大至25 mL当可耐受时。
3. 输注速率–首次输注，至15 mL/hr每部位。可增至最大25 mL/hr每部位可耐受时。然而, 最大输注速率不要超过所有合并输注部位总共50 mL/hr。
剂型和规格：
0.2 g/mL(20%)蛋白皮下注射
禁忌证：
1. 对人免疫球蛋白或Hizentra组分，如聚山梨醇酯80过敏或全身反应。
2. 血脯氨酸过多症(Hizentra含稳定剂L-脯氨酸)。
3. IgA-缺乏有对IgA抗体患者和超敏性史患者。
警告和注意事项：
1. IgA-缺乏有抗-IgA抗体患者是处在严重超敏性和过敏反应高危。如发生超敏反应中断使用。
2. 监查患者用IGIV治疗报道发生的反应，用Hizentra可能发生，包括肾功能不全/衰竭、血栓栓塞事件、,无菌性脑膜炎综合征(AMS)、溶血、和输注相关急性肺损伤(TRALI)。
3. 产品从人血浆制造可能含传染因子，如，病毒和，理论上，克罗伊茨费尔特-雅各布病(CJD)病原体。
不良反应：
最常见不良反应，观察到≥5%研究受试者，是局部反应(即，肿胀、发红、热、疼痛和注射部位痒)、头痛、呕吐、疼痛、和疲乏。
药物相互作用：
被动输注抗体可能：
1. 导致血清学检验结果的误解。
2. 干扰活病毒疫苗的反应
在特殊人群中的使用：
妊娠：无人或动物资料。只有明确需要时使用。
HIZENTRA说明书
Manufacturer:
CSL Behring, LLC
Pharmacological Class:
Immune globulin subcutaneous (human) (IGSC)
Active Ingredient(s):
Immune serum globulin (human) 0.2g/mL (20%); liq for slow SC infusion; contains L-proline, polysorbate-80; preservative-free.
Indication(s):
Primary immunodeficiency, as replacement therapy.
Pharmacology:
Hizentra is an immune globulin (IgG) that is given by subcutaneous (SC) infusion only. It is prepared from pooled human plasma using a process that retains the Fc and Fab functions of the IgG molecule, and it undergoes screening, testing, and manufacturing steps to reduce the risk of viral transmission.
Hizentra provides opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. It is indicated as replacement therapy for primary humoral immunodeficiency, including congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.
Compared to gamma globulin that is administered by IV infusion (IVIG), this product, given as weekly SC infusions, results in relatively stable (lower peak and higher trough) steady-state serum IgG levels.
Clinical Trials:
A prospective, open-label, multicenter, single-arm clinical study was conducted to assess the efficacy, tolerability, and safety of this product in both adult and pediatric patients with primary humoral immunodeficiency. Subjects who had previously received monthly treatment with IVIG were switched to weekly subcutaneous infusions with Hizentra for 15 months (a 12-month efficacy period after a 3-month wash-in/out period). The annual rate of serious bacterial infections (bacterial pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, visceral abscess) was evaluated. In the mean intent-to-treat population of 38 subjects, the annual rate of serious bacterial infections was 0, and the annual rate of any infection was 2.76 infections/subject year. Twenty-seven subjects (71.1%) used prophylactic antibiotics, with an annual rate of 48.5 days/subject year. Also, the use of antibiotics and the days out of work/school, and hospitalizations due to infections were examined. Of 12,605 subject days, 71 days were missed from school or work, with an annual rate of 2.06 days/subject year. The number of days of hospitalization for infections was 7, with an annual rate of 0.2 days/subject year.
Legal Classification:
Rx
Contraindication(s):
IgA-deficiency with IgA antibodies and history of hypersensitivity. Hyperprolinemia. Previous severe reaction to human immune globulin.
Adults & Children:
See literature. Give once weekly by slow (over approx. 1 hour) subcutaneous infusion using infusion pump into abdomen, thigh, upper arm, or lateral hip areas; may use up to 4 sites simultaneously. Start treatment 1 week after last IgG (IGIV) infusion. Obtain serum IgG trough level. Initial dose: (1.53 x previous IVIG dose [in grams])/number of weeks between IGIV doses; max volume of 15mL/site for first dose; may increase to 20–25mL/site for subsequent infusions; max flow rate of 15mL/hour per site for first dose; may increase to 25mL/hour per site for subsequent infusions; max 50mL/hour for all sites combined; reduce infusion rate in renal dysfunction or thrombosis risk. Adjust subsequent doses based on serum IgG trough levels after 2–3 months (see dosing chart in literature) and clinical response. Ensure adequate dose (≥200mg/kg) if exposed to measles.
Precaution(s):
Correct volume depletion, check renal function before and during therapy; discontinue if renal function deteriorates. Diabetes mellitus, overweight, hypovolemia: increased risk of renal dysfunction. Hypertriglyceridemia, advanced age, impaired cardiac output, hypercoagulation, prolonged immobilization, hyperviscosity, monoclonal gammopathies: increased risk of thrombotic events. Monitor for aseptic meningitis, hemolysis, delayed hemolytic anemia, transfusion-related acute lung injury (eg, pulmonary edema, dyspnea, hypoxemia). Antibody formation. Risk of transmission of blood-borne diseases. Elderly. Pregnancy (Cat.C). Nursing mothers.
Interaction(s):
Concomitant nephrotoxic drugs: increased risk of renal toxicity. May affect response to live virus vaccinations. May interfere with serological test interpretation.
Adverse Reaction(s):
Local reactions (eg, swelling, redness, heat, pain, itching), headache, vomiting, pain, fatigue, cough, nausea, rash.
How Supplied:
Single-use vial (5mL, 10mL, 20mL)—1
Last Updated:
4/22/2010
免疫球蛋白替代治疗药Hizentra获准用于治疗原发性免疫缺陷病
2010年3月4日，CSL Behring公司宣布，美国食品药品管理局(FDA)已批准Hizentra用于治疗原发性免疫缺陷病(PI)患者。Hizentra是一种皮下用免疫球蛋白替代治疗药，其市售形式为20%的液体制剂，此浓度高于某些替代药物。对PI患者应用免疫球蛋白替代疗法可能有助于治疗其现有的或慢性感染，并防止发生新的感染。
患者可以使用便携式泵在家自行皮下Hizentra给药。这种人性化制剂可在室温下储存，每周用药一次。
FDA批准Hizentra的依据为一项在美国开展的前瞻性、开放性、多中心、单组临床研究结果，该研究旨在评价Hizentra治疗成人和小儿PI患者的疗效、耐受性以及安全性。在研究中，先前每3周或4周接受1次静脉免疫球蛋白输注治疗的患者换成每周1次Hizentra皮下给药治疗，持续15个月(3个月的洗入或洗脱期后，继以12个月的疗效期)。在38例洗入或洗脱期后接受至少1次输注的患者中分析Hizentra的疗效。
与药物有关的最常见不良反应(即临床研究中所观察到的发生率≥5%)有注射部位局部反应、头痛、呕吐、疼痛以及乏力。
Hizentra禁用于下列人群：对免疫球蛋白制剂或Hizentra成分有过敏反应史或重度全身反应史者；患选择性免疫球蛋白A(IgA)缺陷、已知有针对IgA的抗体及有变态反应史者。若出现疑似Hizentra用药的过敏反应时，应即刻停止输注，并给予患者适当治疗。由于Hizentra含有稳定剂L-脯氨酸，故亦应禁用于患高脯氨酸血症的患者。
Hizentra来源于人血浆。无法完全消除传播病毒等传染源的风险，理论上讲，亦无法完全消除克罗伊茨费尔特-雅各布病的病毒。 | 
