重组阿葡糖苷酶α(Lumizyme，alglucosidase alfa)-治疗庞倍氏症（Pompe）新药
批准日期：2010年5月24日；公司：Genzyme Corporation
适应证和用途：
LUMIZYME(阿葡糖苷酶α)[见一般描述(11)]是一种溶酶体糖原-特异性酶，适用于8岁和以上与后期(非婴幼儿)发病庞贝氏症(Pompe disease，GAA缺乏症)没有心脏肥厚证据患者。尚未在婴幼儿发病患者，或在小于8岁后(非婴幼儿)发病患者的对照临床试验评价LUMIZYME的安全性和有效性。
剂量和给药方法：
LUMIZYME的推荐剂量是20mg/kg体重每2周给药1次，用作静脉输注。
剂型和规格：
剂型：为静脉输注溶液的冻干粉。
规格：5mg/mL。
禁忌证：
无
警告和注意事项：
1) 某些患者在输注LUMIZYME期间有危及生命的过敏反应。当给予LUMIZYME时。确保有适当医疗支持措施，包括容易得到心肺复苏仪器设备。
2) 如发生严重变态或过敏反应，考虑立即停止LUMIZYME给药和开始适当医学治疗。
3) 用阿葡糖苷酶α可能发生严重皮肤和全身免疫介导反应。所以，当接受LUMIZYME时，监查患者是否发生全身免疫复合物反应涉及皮肤和其它器官。
不良反应
临床试验经验
因为临床试验是在控制条件下进行的，观察到不良反应率可能不能预测患者临床实践中观察到的发生率。是基于在一项设计纳入患者年龄8-70岁随机化，双盲，安慰剂-对照研究中，90例患者(45例男性，45例女性)晚发病庞贝氏病，年龄10至70岁，对20 mg/kg LUMIZYME或安慰剂的暴露评估不良反应。最年轻LUMIZYME-治疗患者为16岁，和最年轻安慰剂治疗患者为10岁。所有患者未用国过酶替代治疗。患者按2:1比率被机化并每隔周接受LUMIZYME或安慰剂共78周(18个月)。研究人群在LUMIZYME组中包括34例男性和26例女性(N=60)和安慰剂组11例男性和19例女性(N=30)。2例患者接受LUMIZYME由于过敏反应终止研究。LUMIZYME组3例患者由于继发血栓形成的基底动脉瘤的脑干缺血研究期间死亡，被认为与治疗无关。
在随机化，双盲，安慰剂-对照研究报道的用LUMIZYME严重不良反应包括过敏[见黑框警告和警告和注意事项(5.1)]。过敏反应包括：血管水肿、咽喉发紧和胸痛/不适。1例患者有沃-帕-怀综合征(Wolff-Parkinson-White syndrome)史经受室上性心动过速严重不良反应。LUMIZYME治疗患者相比安慰剂发生率较高的其它严重不良事件包括冠状动脉疾病、椎间盘脱出、肺炎、胃肠炎、和脱水。
最常观察到不良反应是输注反应。输注反应，被定义为输注期间或输注完成后2小时内发生的不良反应，对照研究中LUMIZYME治疗患者发生率较安慰剂≥ 5%。包括过敏、荨麻疹、腹泻、呕吐、呼吸困难、瘙痒、皮疹/红斑、咽喉痛、颈痛、听觉迟钝、脸红/热感、四肢痛、下落(fall)和胸部不适。在其它临床试验和用LUMIZYME扩展准入计划观察到另外输注反应包括呼吸窘迫、咳嗽、网状青斑(livedo reticularis)、焦虑不安、易怒、干呕、强直、震颤和增加流泪。
如发生输注反应，减低输注速率，暂停输注，和/或给予抗组织胺和/或退热药可能减轻症状。如发生严重输注或变态反应，应考虑立即停止LUMIZYME给药，和应开始适当医学治疗[见警告和注意事项(5.1)]。当临床适应时，严重输注反应一般用中断输注、给予抗组织胺、皮质甾体、静脉液体、和/或氧处理。在某些过敏反应情况，给予肾上腺素。曾经受输注反应患者再次给予LUMIZYME治疗时应谨慎。
用LUMIZYME输注也曾观察到迟发病性输注反应。迟发病输注反应，定义为在LUMIZYME输注完成后48小时发生不良反应。在一项对照试验中LUMIZYME治疗患者相比安慰剂治疗患者发生率 ≥ 3%。症状包括荨麻疹、眩晕、程序性疼痛、咽喉痛、不适、肌肉痉挛、肌肉骨骼疼痛、肌肉骨骼软弱、肌肉骨骼僵硬、颈痛、失眠、和鼻衄。应劝告患者延迟发病输注反应的可能性和给予适当随访指导.
庞倍氏症（Pompe），又称2型糖原累积症，是一种罕见的严重肌体衰弱性疾病。该病最终会因人体呼吸功能衰竭而导致死亡，对新生儿的危害尤其严重。目前在美国，患庞倍氏症的患者达4万~30万人.

LUMIZYME® (alglucosidase alfa) is a lysosomal glycogen-specific enzyme indicated for patients 8 years and older with late (non-infantile) onset Pompe disease (GAA deficiency) who do not have evidence of cardiac hypertrophy. The safety and efficacy of LUMIZYME have not been evaluated in controlled clinical trials in infantile-onset patients, or in late (non-infantile) onset patients less than 8 years of age.
IMPORTANT SAFETY INFORMATION
WARNING: ANAPHYLAXIS and RESTRICTED DISTRIBUTION PROGRAM
Life-threatening anaphylactic reactions, severe allergic reactions and immune mediated reactions have been observed in some patients during LUMIZYME infusions. Therefore, appropriate medical support should be readily available when LUMIZYME is administered.
Because of the potential risk of rapid disease progression in Pompe disease patients less than 8 years of age, LUMIZYME is available only through a restricted distribution program called the LUMIZYME ACE Program. Only prescribers and healthcare facilities enrolled in the program may prescribe, dispense, or administer LUMIZYME. LUMIZYME may be administered only to patients who are enrolled in and meet all the conditions of the LUMIZYME ACE Program. To enroll in the LUMIZYME ACE Program call 1-800-745-4447.
Anaphylaxis and Allergic Reactions: Anaphylaxis and severe allergic reactions have been observed in patients during and up to 3 hours after LUMIZYME infusion. Some of the reactions were life-threatening and included anaphylactic shock, respiratory arrest, apnea, dyspnea, bradycardia, tachycardia, and hypotension. Other accompanying reactions included chest discomfort/pain, throat tightness, bronchospasm, wheezing, tachypnea, cyanosis, decreased oxygen saturation/hypoxia, convulsions, angioedema (including tongue or lip swelling, periorbital edema, and face edema), pruritus, rash, urticaria, hyperhidrosis, nausea, dizziness, hypertension, flushing/erythema, fever, pallor, peripheral coldness, feeling hot, restlessness, nervousness, headache, back pain, and paraesthesia. Some of these reactions were IgE-mediated.
If anaphylaxis or other severe allergic reactions occur, immediate discontinuation of the administration of LUMIZYME should be considered, and appropriate medical treatment should be initiated. Severe reactions are generally managed with infusion interruption, administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. In some cases of anaphylaxis, epinephrine has been administered. Because of the potential for severe allergic reactions, appropriate medical support, including cardiopulmonary resuscitation equipment, should be readily available when LUMIZYME is administered. The risk and benefits of re-administering LUMIZYME following an anaphylactic or severe allergic reaction should be considered. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product.
Immune Mediated Reactions: Severe cutaneous reactions have been reported with alglucosidase alfa including necrotizing skin lesions. Systemic immune mediated reactions, including possible type III immune mediated reactions have been observed with alglucosidase alfa. These reactions occurred several weeks to 3 years after initiation of alglucosidase alfa infusions. Skin biopsy in one patient demonstrated deposition of anti-rhGAA antibodies in the lesion. Another patient developed severe inflammatory arthropathy in association with fever and elevated erythrocyte sedimentation rate. Nephrotic syndrome secondary to membranous glomerulonephritis was observed in a few Pompe disease patients treated with alglucosidase alfa who had persistently positive anti-rhGAA IgG antibody titers. In these patients renal biopsy was consistent with immune complex deposition. Patients improved following treatment interruption. It is therefore recommended to perform periodic urinalysis.
Patients should be monitored for the development of systemic immune mediated reactions involving skin and other organs while receiving LUMIZYME. If immune mediated reactions occur, discontinuation of the administration of LUMIZYME should be considered, and appropriate medical treatment initiated. The risks and benefits of re-administering alglucosidase alfa following an immune mediated reaction should be considered. Some patients have successfully been rechallenged and have continued to receive alglucosidase alfa under close clinical supervision.
LUMIZYME ACE Program®: LUMIZYME is available only under a restricted distribution program called the LUMIZYME ACE (Alglucosidase Alfa Control and Education) Program. The purpose of the program is to ensure that the known risks of anaphylaxis and severe allergic reactions and the potential risks of severe cutaneous and systemic immune mediated reactions associated with the use of LUMIZYME are communicated to patients and prescribers. In addition, the program is designed to mitigate the potential risk of rapid disease progression in infantile-onset Pompe disease patients and late (non-infantile) onset Pompe disease patients less than 8 years of age for whom the safety and effectiveness of LUMIZYME have not been evaluated. For information about the ACE Program call 1-800-745-4447.
Risk of Acute Cardiorespiratory Failure: Patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function may be at risk of serious exacerbation of their cardiac or respiratory compromise during infusions. Appropriate medical support and monitoring measures should be readily available during infusions and some patients may require prolonged observation times that should be based on the individual needs of the patient. Acute cardiorespiratory failure has been observed in a few infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of alglucosidase alfa.
Precautions for General/Regional Anesthesia: Administration of general anesthesia can be complicated by the presence of severe cardiac and skeletal (including respiratory) muscle weakness, therefore, caution should be used when administering general anesthesia in Pompe disease patients.
Monitoring: Laboratory Tests: Patients should be monitored for IgG antibody formation every 3 months for 2 years and then annually thereafter. Testing for IgG titers may also be considered if patients develop allergic or other immune mediated reactions. Patients who experience anaphylactic or allergic reactions may also be tested for IgE antibodies to alglucosidase alfa and other mediators of anaphylaxis.
Adverse Reactions:
Serious adverse reactions reported with LUMIZYME in the randomized, double-blind, placebo-controlled study included anaphylaxis. Anaphylactic reactions included: angioedema, throat tightness and chest pain/discomfort. One patient with a history of Wolff-Parkinson-White syndrome experienced a serious adverse reaction of supraventricular tachycardia. Other serious adverse events that occurred in a higher incidence in LUMIZYME treated patients compared to placebo included coronary artery disease, intervertebral disc protrusion, pneumonia, gastroenteritis, and dehydration.
The most common adverse reactions observed in clinical studies were infusion reactions. Infusion reactions, defined as an adverse reaction occurring during the infusion or within 2 hours after completion of the infusion, that occurred in LUMIZYME treated patients at an incidence of ≥ 5% compared to placebo included anaphylaxis, urticaria, diarrhea, vomiting, dyspnea, pruritus, rash/erythema, pharyngolaryngeal pain, neck pain, hypoacusis, flushing/feeling hot, pain in extremity, fall and chest discomfort. Additional infusion reactions observed in other clinical trials and expanded access programs with LUMIZYME included respiratory distress, cough, livedo reticularis, agitation, irritability, retching, rigors, tremor and increased lacrimation.
Delayed onset infusion reactions defined as adverse reactions that occurred within 48 hours after completion of LUMIZYME infusion, occurred in LUMIZYME treated patients at an incidence of ≥ 3% compared to placebo treated patients in a controlled clinical trial. Symptoms included urticaria, dizziness, procedural pain, pharyngolaryngeal pain, malaise, muscle spasms, musculoskeletal pain, musculoskeletal weakness, musculoskeletal stiffness, neck pain, insomnia, and epistaxis. Patients should be counseled about the possibility of delayed onset infusion reactions and given proper follow up instructions.
If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administration of antihistamines and/or antipyretics may ameliorate the symptoms. If severe infusion or allergic reactions occur, immediate discontinuation of the administration of LUMIZYME should be considered, and appropriate medical treatment should be initiated. Patients who have experienced infusion reactions should be treated with caution when they are re-administered LUMIZYME.
In postmarketing experience with LUMIZYME, deaths, and serious adverse reactions have been reported, including anaphylaxis. Adverse events resulting in death reported in the postmarketing setting with LUMIZYME treatment included cardiorespiratory arrest, respiratory failure, hemothorax, pneumothorax, cardiac failure, sepsis, aortic dissection, cerebrovascular accident, and skin necrosis. The most frequently reported serious adverse reactions were infusion reactions. In addition to the infusion reactions reported in clinical trials, the following serious adverse events have been reported in at least 2 patients: dyspnea, respiratory failure, bronchospasm, stridor, decreased oxygen saturation/hypoxia, pharyngeal edema, chest discomfort, chest pain, hypotension, hypertension, erythema, flushing, lung infection, tachycardia, cyanosis, hypersensitivity and abdominal pain. One case of hyperparathyroidism has been reported. Additional adverse drug reactions included proteinuria and nephrotic syndrome.
Immunogenicity: In the randomized, double-blind, placebo-controlled study, all patients with available samples treated with LUMIZYME (N=59, 100%) developed IgG antibodies to alglucosidase alfa. All patients who developed IgG antibodies did so within the first 3 months of exposure (median time to seroconversion was 4 weeks). There was no apparent association between mean or peak IgG antibody titers and the occurrence of adverse reactions. A small number of LUMIZYME treated patients in the postmarketing setting who were evaluated tested positive for presence of alglucosidase alfa-specific IgE antibodies. Some of these patients experienced anaphylaxis. Some patients who tested positive for alglucosidase alfa-specific IgE antibodies were successfully rechallenged with LUMIZYME using a slower infusion rate at lower initial doses and have continued to receive treatment under close clinical supervision. Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for the occurrence of anaphylaxis and severe allergic reactions. Therefore, these patients should be monitored more closely during administration of LUMIZYME.
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