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当前位置:药品说明书与价格首页 >> 综合药讯 >> MYOZYME(alglucosidase,阿尔法注射液)-全球唯一治疗庞培氏病药物

MYOZYME(alglucosidase,阿尔法注射液)-全球唯一治疗庞培氏病药物

2011-01-06 14:07:32  作者:新特药房  来源:中国新特药网天津分站  浏览次数:905  文字大小:【】【】【
简介: Myozyme(通用名:alglucosidase alfa, rhGAA)是首个治疗庞培氏病(Pompe/糖原累积症Ⅱ型)的药物。   美国食品暨药物管理局(FDA)批准了Myozyme的生物制品许可申请(biologics license application ...

治疗糖原累积病的有效药物-Myozyme(通用名,alglucosidase alfa, rhGAA)
Myozyme是由美国马塞诸塞州剑桥市的Genzyme公司生产的首个治疗庞培氏病(Pompe/糖原累积症Ⅱ型-GAA缺乏)的药物。 美国食品暨药物管理局(FDA)批准了Myozyme的生物制品许可申请(biologics license application,BLA)。
Myozyme通过静脉输液给药。在两项独立临床试验中,对39位1个月至3.5岁的患有庞培氏病的婴幼儿的首次给药评估了Myozyme的安全性及有效性。
使用该药治疗的婴幼儿患者与未使用该药的同龄同病况患者的已知高致命性相比,无需侵入型吸氧(invasive ventilatory)维持生命的存活率比预计的明显增高。该药在其他形式庞培氏病中的安全性和有效性,尚未得到充分研究。

对Myozyme最严重的不良反应报道是心脏与肺衰竭及过敏性休克。最常见的反应包括肺炎、呼吸衰竭与呼吸困难、感染及发烧。Myozyme标签中包含的一个加框警告称可能存在威胁生命的过敏反应。

敏性反应的风险:
过敏和过危及生命的严重过敏反应包括过敏性休克,心脏骤停,呼吸困难,低血压,心动过缓,缺氧,支气管痉挛,咽痛,呼吸困难,血管性水肿和荨麻疹。在临床试验和上市后MYOZYME安全经验,约有1%的患者在MYOZYME输液过敏性休克和/或心脏骤停,需要生命支持措施。在临床试验和扩大与MYOZYME访问程序,大约14%的患者与MYOZYME发展,涉及至少2 3身体系统,皮肤,呼吸道或心血管系统的过敏反应。

急性心肺衰竭风险:

急性心肺衰竭需要气管插管和强心剂支持已经观察到72小时后,在婴幼儿发病的庞贝氏症患者MYOZYME与基础心肌肥厚,可能与同MYOZYME静脉注射液输液超载有关。  

输液反应:
最常见的不良反应是需要干预输液有关的反应是发生在20 39(51%)与临床研究MYOZYME治疗的患者。一些反应严重。严重输液反应报告超过1例的临床研究和扩大使用方案包括:发烧,血氧饱和度下降,心动过速,紫绀,低血压等。其他输液反应报告多患者的临床研究和扩大使用方案包括:皮疹,潮红,荨麻疹,发烧,咳嗽,心动过速,血氧饱和度下降,呕吐,呼吸急促,情绪激动,血压上升/高血压,紫绀,烦躁不安,脸色苍白,皮肤瘙痒,干呕,严格要求,震颤,低血压,支气管痉挛,红斑,脸部浮肿,感觉热,头痛,多汗,增加流泪,网状青斑,恶心,眶周水肿,烦躁不安,和喘息。 

免疫介导的反应:

严重的皮肤和全身免疫介导的反应已在上市后的经验与MYOZYME报道,至少有2例。应监测患者的全身免疫复合物介导的包括皮肤和其他器官的反应,同时接受MYOZYME发展。

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原产地英文商品名:
MYOZYME 50MG VIAL
原产地英文药品名:
ALGLUCOSIDASE ALFA
中文参考商品译名:
MYOZYME 50毫克瓶
生产厂家中文参考译名:
Genzyme公司
生产厂家英文名:
Genzyme
---------------------------------------------------------------


部分中文MYOZYME信息资料(仅供参考)

 

MYOZYME(alglucosidase阿尔法)注射液,粉,冻干
[Genzyme公司]
 

MYOZYME ®(alglucosidase阿尔法)
注射,静脉注射使用
初步U. S.批准:2006年

适应症
MYOZYME(alglucosidase阿尔法)是一种溶酶体糖原特定的酶庞贝氏症(GAA缺乏症)患者使用。 MYOZYME已被证明可以改善呼吸机在婴幼儿发病的庞贝氏症患者的生存相比,未经处理的历史对照,而MYOZYME使用其他形式的庞贝氏症患者没有得到充分的研究,以确保安全性和有效性。

剂量和用法
MYOZYME建议剂量是20毫克/公斤体重静脉滴注给药,每2周。
 
剂型和优势
剂型:冻干粉静脉输液。
剂量强度:5毫克/毫升。
禁忌
没有。
警告和注意事项
危及生命的过敏反应,严重的过敏反应和免疫介导的反应已经观察到在三小时内MYOZYME输注后在部分患者。确保适当的医疗保障措施,包括心肺复苏设备,都是现成的管理MYOZYME时。如果发生严重的过敏反应或过敏性反应,考虑立即停止MYOZYME管理,并采取适当的医疗。
在MYOZYME注入心脏或呼吸功能损害患者需要额外的监控。急性心肺功能衰竭,需要插管和肌力的支持已被观察到长达72小时后输液。
在全身麻醉的中央静脉导管放置在婴幼儿发病的庞贝氏疾病患者的心肌肥厚,心律失常,导致心脏骤停或死亡,或需要心脏复苏或除颤已观察。管理心肌肥厚的婴幼儿发病的庞贝氏疾病患者在全身麻醉时,应谨慎使用。
严重的皮肤和全身免疫介导的反应可能会发生的MYOZYME。因此,监测患者的全身免疫复合物介导的反应涉及皮肤和其他器官,而接收MYOZYME发展。
不良反应
治疗最常见的严重不良反应与MYOZYME临床研究中观察到的(> 10%的患者发生),肺炎,呼吸衰竭,呼吸窘迫,导管相关性感染,呼吸道合胞病毒感染,肠胃炎及发烧。
需要干预的最常见的反应是输液反应。
 
在特殊人群中使用
怀孕:医生鼓励参加庞贝氏注册表怀孕的患者。
哺乳母亲:鼓励医师参加护理患者庞贝氏注册表。
修订日期:06/2010

Genzyme公司宣布,FDA已批准Myozyme (alglucosidase alfa)的上市申请。Myozyme用于治疗庞培氏症,这是第一种获准治疗遗传性肌肉疾病的药物。据预计,全球约有1万名庞培氏症患者。

庞培氏症患者有多种临床症状。最典型的症状为肌无力和呼吸困难(所有的患者都会出现这类症状),但病情的轻重取决于患者的发病年龄以及受影响器官的范围。若患儿在出生后几个月即发病,则心脏受影响的面积较大,且通常在满周岁之前死亡。

若在儿童时期、青少年时期或成年后发病,患者的病情则会逐渐加重,并且会由于呼吸衰竭而在早年死亡。为了保证患者呼吸畅通,在他们周围通常要进行机械通风,并且他们需借助轮椅进行活动。

此前,Myozyme已被FDA指定为罕见病用药,它将享有7年的独家销售权。Genzyme公司打算在两周内即在美国推出该药。上个月,该药也刚通过欧盟的批准。

Myozyme
Generic Name: alglucosidase alfa
Dosage Form: injection, powder, lyophilized, for solution

FULL PRESCRIBING INFORMATION

Warning
Life-threatening anaphylactic reactions, severe allergic reactions and immune mediated reactions have been observed in some patients during Myozyme infusions. Therefore, appropriate medical support should be readily available when Myozyme is administered. [see Warnings and Precautions (5.1)]
Risk of Cardiorespiratory Failure
Patients with compromised cardiac or respiratory function may be at risk for serious acute exacerbation of their cardiac or respiratory compromise due to infusion reactions, and require additional monitoring. [see Warnings and Precautions (5.2)]

Indications and Usage for Myozyme

Myozyme® (alglucosidase alfa) [see Description (11)]  is a lysosomal glycogen-specific enzyme indicated for use in patients with Pompe disease (GAA deficiency). Myozyme has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to an untreated historical control, whereas use of Myozyme in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy [see Clinical Studies (14) ].

Myozyme Dosage and Administration

Recommended Dose

The recommended dosage regimen of Myozyme is 20 mg/kg body weight administered every 2 weeks as an intravenous infusion.

Instructions for Use

Myozyme does not contain any preservatives.  Vials are single-use only.  Any unused product should be discarded.

The total volume of infusion is determined by the patient’s body weight and should be administered over approximately 4 hours.  

Infusions should be administered in a step-wise manner using an infusion pump. The initial infusion rate should be no more than 1 mg/kg/hr. The infusion rate may be increased by 2 mg/kg/hr every 30 minutes, after patient tolerance to the infusion rate is established, until a maximum rate of 7 mg/kg/hr is reached. Vital signs should be obtained at the end of each step. If the patient is stable, Myozyme may be administered at the maximum rate of 7 mg/kg/hr until the infusion is completed. The infusion rate may be slowed and/or temporarily stopped in the event of infusion reactions. See Table 1 below for the rate of infusion at each step, expressed as mL/hr based on the recommended infusion volume by patient weight.

Table 1. Recommended Infusion Volumes and Rates
Patient Weight Range (kg)   Total infusion volume (mL) 

Step 1

1 mg/kg/hr

(mL/hr) 

Step 2

3 mg/kg/hr

(mL/hr) 

Step 3

5 mg/kg/hr 

(mL/hr) 

Step 4

7 mg/kg/hr

(mL/hr) 
1.25 - 10 50 3 8 13 18
10.1 - 20 100 5 15 25 35
20.1 - 30 150 8 23 38 53
30.1 - 35 200 10 30 50 70
35.1 - 50 250 13 38 63 88
50.1 - 60 300 15 45 75 105
60.1 - 100 500 25 75 125 175
100.1 - 120 600 30 90 150 210
120.1 - 140 700 35 105 175 245
140.1 - 160 800 40 120 200 280
160.1 - 180 900 45 135 225 315
180.1 - 200 1000 50 150 250 350
Reconstitution, dilution and administration

Myozyme should be reconstituted, diluted and administered by a health care professional.

Use aseptic technique during preparation. Do not use filter needles during preparation.

  1. Determine the number of vials to be reconstituted based on the individual patient’s weight and the recommended dose of 20 mg/kg.    

    Patient weight (kg) x dose (mg/kg) = patient dose (in mg)

    Patient dose (in mg) divided by 50 mg/vial = number of vials to reconstitute. If the number of vials includes a fraction, round up to the next whole number.

    Example: Patient weight (16 kg) x dose (20 mg/kg) = patient dose (320 mg)

    320 mg divided by 50 mg/vial = 6.4 vials; therefore, 7 vials should be reconstituted

    Remove the required number of vials from the refrigerator and allow them to reach room temperature prior to reconstitution (approximately 30 minutes).
  2. Reconstitute each Myozyme vial by slowly injecting 10.3 mL of Sterile Water for Injection, USP to the inside wall of each vial. Each vial will yield 5 mg/mL. The total extractable dose per vial is 50 mg per 10 mL. Avoid forceful impact of the water for injection on the powder and avoid foaming. This is done by slow drop-wise addition of the water for injection down the inside of the vial and not directly onto the lyophilized cake. Tilt and roll each vial gently. Do not invert, swirl, or shake. 
  3. The reconstituted Myozyme solution should be protected from light.
  4. Perform an immediate visual inspection on the reconstituted vials for particulate matter and discoloration. If upon immediate inspection opaque particles are observed or if the solution is discolored do not use. The reconstituted solution may occasionally contain some alglucosidase alfa particles (typically less than 10 in a vial) in the form of thin white strands or translucent fibers subsequent to the initial inspection. This may also happen following dilution for infusion. These particles have been shown to contain alglucosidase alfa and may appear after the initial reconstitution step and increase over time. Studies have shown that these particles are removed via in-line filtration without having a detectable effect on the purity or strength.
  5. Myozyme should be diluted in 0.9% Sodium Chloride for Injection, USP, immediately after reconstitution, to a final Myozyme concentration of 0.5 to 4 mg/mL. See Table 1 for the recommended total infusion volume based on patient weight.
  6. Slowly withdraw the reconstituted solution from each vial. Avoid foaming in the syringe.
  7. Remove airspace from the infusion bag to minimize particle formation due to the sensitivity of Myozyme to air-liquid interfaces.
  8. Add the reconstituted Myozyme solution slowly and directly into the sodium chloride solution. Do not add directly into airspace that may remain within the infusion bag. Avoid foaming in the infusion bag.
  9. Gently invert or massage the infusion bag to mix. Do not shake. 
  10. Administer Myozyme using an in-line low protein binding 0.2 µm filter. 

Myozyme should not be infused in the same intravenous line with other products.

Myozyme does not contain any preservatives. Vials are single-use only. Discard any unused product.

Dosage Forms and Strengths

Myozyme is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder for reconstitution with Sterile Water for Injection, USP to yield a concentration of 5 mg/mL; and then further diluted with 0.9% Sodium Chloride for Injection, USP for intravenous infusion.

Single use vials are available in 50 mg dosage only.

Contraindications

None.

Warnings and Precautions

Anaphylaxis and Allergic Reactions (see Boxed Warning)

Anaphylaxis and severe allergic reactions have been reported in some patients during and up to three hours after Myozyme infusion some of which were IgE-mediated.  Some of the reactions were life-threatening and included: anaphylactic shock, cardiac arrest, respiratory distress, hypotension, bradycardia, hypoxia, bronchospasm, throat tightness, dyspnea, angioedema, and urticaria. Interventions have included: cardiopulmonary resuscitation, mechanical ventilatory support, oxygen supplementation, intravenous (IV) fluids, hospitalization, treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids. [see Adverse Reactions (6)].

In clinical trials and postmarketing safety experience with Myozyme, approximately 1% of patients developed anaphylactic shock and/or cardiac arrest during Myozyme infusion that required life-support measures. In clinical trials and expanded access programs with Myozyme, approximately 14% of patients treated with Myozyme have developed allergic reactions that involved at least 2 of 3 body systems, cutaneous, respiratory or cardiovascular systems.  These events included: Cardiovascular: hypotension, cyanosis, hypertension, tachycardia, ventricular extrasystoles, bradycardia, pallor, flushing, nodal rhythm, peripheral coldness; Respiratory: tachypnea, wheezing/bronchospasm, rales, throat tightness, hypoxia, dyspnea, cough, respiratory tract irritation, decreased oxygen saturation; Cutaneous: angioedema, urticaria, rash, erythema, periorbital edema, pruritus, hyperhidrosis, cold sweat, livedo reticularis [see Adverse Reactions (6)].

If anaphylactic or other severe allergic reactions occur, immediate discontinuation of the administration of Myozyme should be considered, and appropriate medical treatment should be initiated. Because of the potential for severe allergic reactions, appropriate medical support measures, including cardiopulmonary resuscitation equipment, should be readily available when Myozyme is administered.

The risks and benefits of re-administering Myozyme following an anaphylactic or severe allergic reaction should be considered.  Some patients have been rechallenged and have continued to receive Myozyme under close clinical supervision. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product [see Adverse Reactions (6.3)].

Risk of Acute Cardiorespiratory Failure (see Boxed Warning)

Acute cardiorespiratory failure requiring intubation and inotropic support has been observed up to 72 hours after infusion with Myozyme in infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of Myozyme [see Instructions for Use (2.2)]. Patients with acute underlying respiratory illness, compromised cardiac function and/or sepsis 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 Myozyme infusion, and infants with cardiac dysfunction may require prolonged observation times that should be individualized based on the needs of the patient [see Dosage and Administration (2.2)].

Risk of Cardiac Arrhythmia and Sudden Cardiac Death During General Anesthesia for Central Venous Catheter Placement

Cardiac arrhythmia, including ventricular fibrillation, ventricular tachycardia and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been observed in infantile-onset Pompe disease patients with cardiac hypertrophy, associated with the use of general anesthesia for the placement of a central venous catheter intended for Myozyme infusion.

Caution should be used when administering general anesthesia for the placement of a central venous catheter in infantile-onset Pompe disease patients with cardiac hypertrophy.

Infusion Reactions

Infusion reactions occurred in 20 of 39 (51%) of patients treated with Myozyme in clinical studies [see Adverse Reactions (6)]. Some reactions were severe.  Severe infusion reactions reported in more than 1 patient in clinical studies and the expanded access program included: fever, decreased oxygen saturation, tachycardia, cyanosis and hypotension. Other infusion reactions reported in more than 1 patient in clinical studies and the expanded access program included: rash, flushing, urticaria, fever, cough, tachycardia, decreased oxygen saturation, vomiting, tachypnea, agitation, increased blood pressure/hypertension, cyanosis, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face edema, feeling hot, headache, hyperhidrosis, increased lacrimation, livedo reticularis, nausea, periorbital edema, restlessness and wheezing. Some patients were pre-treated with antihistamines, antipyretics and/or steroids. Infusion reactions occurred in some patients after receiving antipyretics, antihistamines, or steroids. Infusion reactions may occur at any time during, or up to 2 hours after, the infusion of Myozyme, and are more likely with higher infusion rates.

Patients with advanced Pompe disease may have compromised cardiac and respiratory function, which may predispose them to a higher risk of severe complications from infusion reactions. Therefore, these patients should be monitored more closely during administration of Myozyme. Patients with an acute illness at the time of Myozyme infusion may be at greater risk for infusion reactions. Careful consideration should be given to the patient’s clinical status prior to administration of Myozyme.

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 Myozyme should be considered, and appropriate medical treatment should be initiated [see Adverse Reactions (6.1)]. Severe infusion reactions are generally managed with infusion interruption, administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. Patients who have experienced infusion reactions should be treated with caution when they are re-administered Myozyme.

Immune Mediated Reactions

Severe cutaneous and systemic immune mediated reactions have been reported in postmarketing safety experience with Myozyme in at least 2 patients, including ulcerative and necrotizing skin lesions, and possible type III immune complex-mediated reactions [see Adverse Reactions (6.3)]. These reactions occurred several weeks to 3 years after initiation of Myozyme infusions. Skin biopsy in one patient demonstrated deposition of anti-rh-GAA antibodies in the lesion.  Another patient developed severe inflammatory arthropathy in association with fever and elevated erythrocyte sedimentation rate. Patients should be monitored for the development of systemic immune complex-mediated reactions involving skin and other organs while receiving Myozyme. If immune mediated reactions occur, discontinuation of the administration of Myozyme 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.

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. 

There are no marketed tests for antibodies against alglucosidase alfa. Contact your local Genzyme representative or Genzyme Corporation at 1-800-745-4447 for information on testing and to obtain a sample collection box.

Results from 2 intravenous repeated-dose animal toxicology studies using doses of 100 or 200 mg/kg Myozyme (about 1.6 to 3.2 times the recommended human dose based on body surface area) in Cynomolgus monkeys to evaluate the possibility of liver accumulation over time showed GAA levels above background in liver tissue several days following the last dose; however, no concurrent changes in liver enzymes or histopathology were observed. Liver enzymes should be evaluated prior to the initiation of Myozyme treatment and periodically thereafter.

Adverse Reactions

Clinical Trial Experience

Because clinical trials are conducted under more controlled conditions, the observed adverse reaction rates may not predict the rates observed in patients in clinical practice. The data described below reflect exposure of 39 Pompe disease patients to 20 or 40 mg/kg of Myozyme administered every other week in 2 separate clinical trials for periods ranging from 1 to 106 weeks (mean 61 weeks). Patients were ages 1 month to 3.5 years at first treatment. The population was nearly evenly distributed in gender (18 females and 21 males).

The most serious adverse reactions reported with Myozyme were anaphylactic reactions, acute cardiorespiratory failure, and cardiac arrest.

Anaphylactic reactions have been reported during and within 3 hours after Myozyme infusion [see Boxed Warning and Warnings and Precautions (5.1)].

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 [see Boxed Warning  and Warnings and Precautions (5.2) and Instructions for Use (2.2)].

The most common serious treatment-emergent adverse reactions occurring in >10% of patients observed in clinical studies with Myozyme were pneumonia, respiratory failure, respiratory distress, catheter-related infection, respiratory syncytial virus infection, gastroenteritis and fever.

The most common adverse reactions requiring intervention in clinical trials were infusion reactions [see Warnings and Precautions (5.4)].  Twenty of 39 patients (51%) treated with Myozyme in clinical studies developed 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 more than 1 patient in clinical studies and the expanded access program include rash, flushing, urticaria, fever, cough, tachycardia, decreased oxygen saturations, vomiting, tachypnea, agitation, increased blood pressure, cyanosis, hypertension, irritability, pallor, pruritus, retching, rigors, tremor, hypotension, bronchospasm, erythema, face edema, feeling hot, headache, hyperhidrosis, increased lacrimation, livedo reticularis, nausea, periorbital edema, restlessness, and wheezing.

The most common treatment-emergent adverse reactions occurring in ≥ 20% of patients were fever, diarrhea, rash, vomiting, cough, pneumonia, otitis media, upper respiratory tract infection, gastroenteritis and decreased oxygen saturation.

Table 2 enumerates treatment-emergent adverse reactions that occurred in at least 20% of patients treated with Myozyme in clinical trials described above. Reported frequencies of adverse events have been classified by MedDRA terms.

Table 2. Summary of Adverse Reactions by System Organ Class and Preferred Term Occurring in at Least 20% of Patients Treated with Myozyme® in Clinical Trials
 

System Organ Class

            Preferred Term 

Number of Patients

(N=39)
n (%) 

 

Number of Adverse Events

Any Adverse Events =   39 (100)  1859
General disorders and administration site conditions   38 (97)  
        Pyrexia  36 (92)  169
Respiratory, thoracic and mediastinal disorders   38 (97)   
        Cough  18 (46)  69
        Respiratory distress  13 (33)  18
        Respiratory failure  12 (31)  24
        Rhinorrhea 11 (28) 16
        Tachypnea 9 (23) 15
Infections and infestations 37 (95)
        Pneumonia 18 (46) 43
        Otitis media 17 (44) 35
        Upper respiratory tract infection 17 (44) 39
        Gastroenteritis 16 (41) 17
        Pharyngitis 14 (36) 26
        Ear infection 13 (33) 23
        Oral candidiasis 12 (31) 20
        Catheter-related infection 11 (28) 15
        Bronchiolitis 9 (23) 10
        Nasopharyngitis 9 (23) 25
Gastrointestinal disorders 32 (82)
        Diarrhea 24 (62) 62
        Vomiting 19 (49) 62
        Gastroesophageal reflux disease 10 (26) 13
        Constipation 9 (23) 14
Skin and subcutaneous tissue disorders 32 (82)
        Rash 21 (54) 72
        Diaper dermatitis 14 (36) 34
        Urticaria 8 (21) 25
Investigations 28 (72)
        Oxygen saturation decreased 16 (41) 44
Cardiac disorders 24 (62)
        Tachycardia 9 (23) 31
        Bradycardia 8 (21) 18
Injury, poisoning and procedural complications 22 (56)
        Post procedural pain 10 (26) 20
Blood and lymphatic system disorders 17 (44)
        Anemia 12 (31) 23
Vascular disorders 14 (36)
        Flushing 8 (21) 15

Five additional juvenile-onset Pompe disease patients were evaluated in a single-center, open-label, non-randomized, uncontrolled clinical trial. Patients were ages 5 to 15 years, ambulatory (able to walk at least 10 meters in 6 minutes), and not receiving invasive ventilatory support at study entry. All 5 patients received treatment with 20 mg/kg Myozyme for 26 weeks. The most common treatment-emergent adverse reactions observed with Myozyme treatment in this study were headache (4.1%), pharyngitis (9.1%), upper abdominal pain (15.2%), malaise (6.1%) and rhinitis (6.1%).

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The majority of patients (34 of 38; 89%) in the two clinical trials tested positive for IgG antibodies to alglucosidase alfa. The data reflect the percentage of patients whose test results were considered positive for antibodies to alglucosidase alfa using an enzyme-linked immunosorbent assay (ELISA) and radioimmunoprecipitation (RIP) assay for alglucosidase alfa-specific IgG antibodies.  Most patients who develop antibodies do so within the first 3 months of exposure. There is evidence to suggest that patients developing sustained titers ≥12,800 of anti-alglucosidase alfa antibodies may have a poorer clinical response to treatment, or may lose motor function as antibody titers increase. Treated patients who experience a decrease in motor function should be tested for neutralization of enzyme uptake or activity. Five patients with antibody titers ≥12,800 at Week 12 had an average increase in clearance of 50% from Week 1 to Week 12 [see Clinical Pharmacology (12.3)]. 

Some patients who developed IgG antibodies to alglucosidase alfa in clinical studies or in the postmarketing setting were evaluated for the presence of inhibitory antibodies and tested positive for inhibition of enzyme activity and/or uptake in in vitro assays.

The effect of antibody development on the long-term efficacy of Myozyme is not fully understood. However, CRIM negative infants have shown poorer clinical response in the presence of high sustained IgG antibody titers and positive inhibitory antibodies.

Infusion reactions were reported in 20 of 39 patients (51%) treated with Myozyme in clinical studies and appear to be more common in antibody-positive patients: 8 of 15 patients with high antibody titers experienced infusion reactions whereas none of 3 antibody-negative patients experienced infusion reactions [see Warnings and Precautions (5.4)].

Patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for the occurrence of anaphylaxis and severe allergic reactions [see Warnings and Precautions (5.1)]. Therefore, these patients should be monitored more closely during administration of Myozyme.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Myozyme. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In postmarketing experience with Myozyme, severe and serious infusion reactions have been reported, some of which were life-threatening, including anaphylactic shock [see Boxed Warning and Warnings and Precautions (5.1)].  Acute cardiorespiratory failure, possibly associated with fluid overload, has been reported in infantile-onset Pompe disease patients with pre-existing hypertrophic cardiomyopathy [see Boxed Warning and Warning and Precautions (5.2)].  In addition to the infusion reactions reported in clinical trials and expanded access programs, the following infusion reactions have been reported in patients during postmarketing use of Myozyme: cardiac arrest, respiratory arrest, apnea, stridor, pharyngeal edema, peripheral edema, chest pain, chest discomfort, muscle spasm, fatigue and conjunctivitis [see Warnings and Precautions (5.1) and (5.4)]. Systemic and cutaneous immune mediated reactions, including ulcerative and necrotizing skin lesions have been reported [see Warnings and Precautions (5.5)].

Drug Interactions

Interference with Other Drugs

No drug interaction or in vitro metabolism studies were performed.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects

Pregnancy Category B. Reproduction studies have been performed in pregnant mice at intravenous doses up to 40 mg/kg/day (plasma AUC of 64.6 mg•min/mL, 0.4 times the human steady-state exposure at the recommended bi-weekly dose) and pregnant rabbits at intravenous doses up to 40 mg/kg/day (plasma AUC of 85 mg•min/mL, 0.5 times the human steady-state exposure at the recommended bi-weekly dose) and have revealed no evidence of impaired fertility or harm to the fetus due to Myozyme. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Women of childbearing potential are encouraged to enroll in the Pompe Registry. [see Patient Counseling Information (17)].

Labor and Delivery

Information on the effect of Myozyme on labor and delivery is unknown. Pregnant women are encouraged to enroll in the Pompe Registry [see Patient Counseling Information (17)].

Nursing Mothers

It is not known whether Myozyme is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Myozyme is administered to a nursing woman.  Nursing women are encouraged to enroll in the Pompe Registry [see Patient Counseling Information (17)].

Pediatric Use

Pediatric patients aged 1 month to 3.5 years at time of first infusion have been treated with Myozyme in clinical trials [see Clinical Studies (14)]. Other open-label clinical trials of Myozyme have been performed in older pediatric patients ranging from 2 to 16 years at the initiation of treatment (juvenile-onset Pompe disease); however the risks and benefits of Myozyme treatment have not been established in the juvenile-onset Pompe disease population.

Geriatric Use

Clinical studies did not include any subjects aged 65 years and older. It is not known whether they respond differently than younger subjects. [see Clinical Studies (14)].

Overdosage

There have been no reports of overdose with Myozyme. In clinical trials, patients received doses up to 40 mg/kg of body weight.

Myozyme Description

Myozyme (alglucosidase alfa), a lysosomal glycogen-specific enzyme, consists of the human enzyme acid α-glucosidase (GAA), encoded by the most predominant of nine observed haplotypes of this gene. Myozyme is produced by recombinant DNA technology in a Chinese hamster ovary cell line. The Myozyme manufacturing process differs from that for LUMIZYME, resulting in differences in some product attributes. Alglucosidase alfa degrades glycogen by catalyzing the hydrolysis of α‑1,4‑ and α‑1,6‑ glycosidic linkages of lysosomal glycogen.

Alglucosidase alfa is a glycoprotein with a calculated mass of 99,377 daltons for the polypeptide chain, and a total mass of approximately 110 kilo Daltons, including carbohydrates.  Alglucosidase alfa has a specific activity of 3 to 5 U/mg (one unit is defined as that amount of activity that results in the hydrolysis of 1 µmole of synthetic substrate per minute under the specified assay conditions). Myozyme is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder for reconstitution with 10.3 mL Sterile Water for Injection, USP. Each 50 mg vial contains 52.5 mg alglucosidase alfa, 210 mg mannitol, 0.5 mg polysorbate 80, 9.9 mg sodium phosphate dibasic heptahydrate, 31.2 mg sodium phosphate monobasic monohydrate. Following reconstitution as directed, each vial contains 10.5 mL reconstituted solution and a total extractable volume of 10 mL at 5.0 mg/mL alglucosidase alfa.  Myozyme does not contain preservatives; each vial is for single use only.

Myozyme - Clinical Pharmacology

Mechanism of Action

Pompe disease (glycogen storage disease type II, GSD II, glycogenosis type II, acid maltase deficiency) is an inherited disorder of glycogen metabolism caused by the absence or marked deficiency of the lysosomal enzyme GAA.

Myozyme provides an exogenous source of GAA.  Binding to mannose-6-phosphate receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalized and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity. It then exerts enzymatic activity in cleaving glycogen.

Pharmacokinetics

The pharmacokinetics of alglucosidase alfa were evaluated in 13 patients of age ranging from 1 month to 7 months with infantile-onset Pompe disease who received 20 mg/kg (as an approximate 4-hour infusion) or 40 mg/kg (as an approximate 6.5-hour infusion) of Myozyme every 2 weeks. The measurement of alglucosidase alfa plasma concentration was based on an activity assay using an artificial substrate.  Systemic exposure was approximately dose proportional between the 20 and 40 mg/kg doses. Based on the pharmacokinetic blood samples collected for 12 hours after a 4-hr intravenous infusion of 20 mg/kg (n=5), the estimated mean AUC was 811 mcg•hr/mL with 17% coefficient of variation [CV], Cmax 162 mcg/mL with 19% CV, clearance 25 mL/hr/kg with 16% CV, and half-life 2.3 hr with 17% CV.

The pharmacokinetics of alglucosidase alfa were also evaluated in a separate trial in 14 patients of age ranging from 6 months to 3.5 years with Pompe disease who received 20 mg/kg of Myozyme as an approximate 4-hour infusion every 2 weeks. The pharmacokinetic parameters were similar to those observed for the 20 mg/kg dose group in the trial of patients of age ranging from 1 month to 7 months.

Nineteen of 21 patients who received treatment with Myozyme and had pharmacokinetics and antibody titer data available at Week 12 developed antibodies to alglucosidase alfa. Five patients with antibody titers ≥ 12,800 at Week 12 had an average increase in clearance of 50% (range 5% to 90%) from Week 1 to Week 12. The other 14 patients with antibody titers < 12,800 at Week 12 had similar average clearance values at Week 1 and Week 12.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Myozyme.

Myozyme at intravenous doses up to 40 mg/kg, administered every other day (plasma AUC of 64.6 mg•min/mL, 0.4 times the human steady-state exposure at the recommended bi-weekly dose) had no effect on fertility and reproductive performance in mice.

Clinical Studies

The safety and efficacy of Myozyme were assessed in 2 separate clinical trials in 39 Pompe disease patients, who ranged in age from 1 month to 3.5 years at the time of first infusion.

Study 1 was an international, multicenter, open-label, clinical trial of 18 infantile-onset Pompe disease patients. This study was conducted between 2003 and 2005. Patients were randomized equally to either 20 mg/kg or 40 mg/kg Myozyme every two weeks, with length of treatment ranging from 52 to 106 weeks. Enrollment was restricted to patients ages 7 months or less at first infusion with clinical signs of Pompe disease, with cardiac hypertrophy, and who did not require ventilatory support at study entry.

Efficacy was assessed by comparing the proportions of Myozyme-treated patients who died or needed invasive ventilator support with the mortality experience of an historical cohort of untreated infantile-onset Pompe patients with similar age and disease severity. In the historical cohort, 61 untreated patients with infantile-onset Pompe disease diagnosed by age 6 months, born between 1982 and 2002, were identified by a retrospective review of medical charts. By the age of 18 months, only one of the 61 historical control patients was alive (98% mortality).

Within the first 12 months of treatment, 3 of 18 Myozyme-treated patients required invasive ventilatory support (17%, with 95% confidence interval 4% to 41%); there were no deaths. With continued treatment beyond 12 months, 4 additional patients required invasive ventilatory support, after receiving between 13 and 18 months of Myozyme treatment; 2 of these 4 patients died after receiving 14 and 25 months of treatment, and after receiving 11 days and 7.5 months of invasive ventilatory support, respectively. No other deaths were reported through a median follow-up of 20 months. Survival without invasive ventilatory support was greater in the Myozyme-treated patients (83%) as compared with overall survival in the historical control group (2%). No differences in outcome were observed between patients who received 20 mg/kg versus 40 mg/kg.

Other outcome measures in this study included unblinded assessments of motor function by the Alberta Infant Motor Scale (AIMS). The AIMS is a measure of infant motor performance that assesses motor maturation of the infant through age 18 months and is validated for comparison to normal, healthy infants.  AIMS-assessed gains in motor function occurred in 13 patients.  In the majority of patients, motor function was substantially delayed compared to normal infants of comparable age. The continued effect of Myozyme treatment over time on motor function is unknown. Two of 9 patients who had demonstrated gains in motor function after 12 months of Myozyme treatment and continued to be followed regressed despite treatment.

Changes from baseline to Month 12 in left ventricular mass index (LVMI), an evaluation of bioactivity, were measured by echocardiography. For the 15 patients with both baseline and Month 12 echocardiograms, all had decreases from baseline in LVMI (mean decrease 118 g/m2, range 45 to 193 g/m2). The magnitude of the decrease in LVMI did not correlate with the clinical outcome measure of ventilator-free survival.

Study 2 was an international, multicenter, non-randomized, open-label clinical trial that enrolled 21 patients who were ages 3 months to 3.5 years at first treatment. All patients received 20 mg/kg Myozyme every other week for up to 104 weeks. Five of 21 patients were receiving invasive ventilatory support at the time of first infusion.

The primary outcome measure was the proportion of patients alive at the conclusion of treatment. At the 52–week interim analysis, 16 of 21 patients were alive. Sixteen patients were free of invasive ventilatory support at the time of first infusion: of these, 4 died, 2 required invasive ventilatory support, and 10 were free of invasive ventilatory support after 52 weeks of treatment. For the 5 patients who were receiving invasive ventilatory support at baseline, 1 died, and 4 remained on invasive ventilatory support at Week 52. The status of patients at Week 52 overlapped with that of an untreated historical group of patients, and no effect of Myozyme treatment could be determined.

How Supplied/Storage and Handling

Myozyme 50 mg vials are supplied as a sterile, nonpyrogenic, white to off-white lyophilized cake or powder. Myozyme is supplied in single-use, clear Type I glass 20 mL (cc) vials.  The closure consists of a siliconized butyl stopper and an aluminum seal with a plastic flip-off cap.

Store Myozyme under refrigeration between 2° to 8°C (36° to 46°F). Do not use Myozyme after the expiration date on the vial.

The reconstituted and diluted solution should be administered without delay. If immediate use is not possible, the reconstituted and diluted solution is stable for up to 24 hours at 2° to 8°C (36° to 46°F).  Storage of the reconstituted solution at room temperature is not recommended. The reconstituted and diluted Myozyme solution should be protected from light. DO NOT FREEZE OR SHAKE.

NDC 58468-0150-1

Patient Counseling Information

Pompe Registry

Patients and their caregivers should be informed that a registry for patients with Pompe disease (the Pompe Registry) has been established in order to better understand the variability and progression of Pompe disease and to continue to monitor and evaluate long-term treatment effects of alglucosidase alfa. The Pompe Registry will also monitor the effects of alglucosidase alfa on pregnant women and their offspring [see Use in Specific Populations (8)]. Patients and their caregivers are encouraged to participate in the Pompe Registry and should be advised that their participation is voluntary and may involve long-term follow-up. Information regarding the registry program visit www.pomperegistry.com or call 1-800-745-4447

General Clinical Recommendations

Patients and caregivers should be informed that anaphylactic reactions, severe allergic reactions, and immune mediated reactions have been observed in some patients having received Myozyme infusions. Patients and caregivers should also be warned of the risk for acute cardiorespiratory failure, cardiac arrhythmias, and infusion reactions. [see Boxed Warning and Warnings and Precautions (5)].

Myozyme is manufactured and distributed by:
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
1-800-745-4447

US License Number: 1596
Myozyme and Genzyme are registered trademarks of Genzyme Corporation
LUMIZYME is a trademark of Genzyme Corporation.

Package Carton–Principle Dispay Panel–50 mg Carton

Package contains one vial of

Myozyme®

(alglucosidase alfa)

50 mg

Store Refrigerated At 2-8°C (36-46°F)

心肌糖原沉积病[庞培氏(Pompe)病]

心肌糖厚沉积病由Pompe(1932)提出,为糖原合成和分解代谢中所需一系列酶的缺陷所致病变,是一种先天性代谢病,本病罕见,是引起婴儿心脏迅速增大的疾病之一,亦即所谓特发性心脏肥大。
[病因]
为糖原分解酶(如a-1,4-葡萄糖苷酶)的缺陷,不能分解为葡萄糖而造成糖原质和量的代谢障碍,使组织中的糖原累积,因此近年把这类疾患总称为糖原沉积病,由于受累的组织或器官不同,可区别为+或+ -型,绝大多数与常染色体隐性遗传有关。实际上可分为肝,心,肌肉三大类,如1型称为肝糖原沉积病(GSDI 亦称VonGierke病),2型为心肌糖原沉积病(GSDI,pampe病等)。3型即肌性糖原沉积病。
[病理]
由于组织中糖原积累,造成器官的肿大与功能不全,如心脏明显增大,主要是心室壁增厚,左室可厚达30毫米(正常为7~10毫米)糖原代谢了肌纤维,并有空泡形成,退行性坏死,但无炎症改变,同时可累及肝,肾和有纹肌等。
[临床情况]
1.病人出生后数周或数月发病,男女相等,病情发展快,常早年死于心力衰竭或呼吸道感染,但也有见于成人者。
2.心脏明显增大但一般无杂音,肌肉软弱无力,巨舌,面容与呆小症或伸舌痴愚相似,肝脾肿大常不明显。
3.胃纳差,呕吐,呼吸困难,紫绀,水肿以及营养不良,发育迟缓等表现。
4.心电图左心肥厚,T波倒置,S~T段下降,血液检查末梢白细胞的酸性麦芽糖酶(葡萄糖苷酶)的活性显著降低。
[X线表现]
心脏呈对称性的原形或球形明显扩大,主要是心室,不侵犯心房,搏动减弱,并可压迫左上支气管,引起左上叶肺不张,晚期有时合并肺郁血或肺炎的表现。
2,心血管造影,显示左心室壁增厚,血液循环正常,有时左肺动脉压升高。
[鉴别诊断]
应与心内膜弹力纤维增生症鉴别,二者X线表现大致相同,又可并存。其它如支气管肺炎伴心力衰竭,先天性心血管畸形,心肌炎等相区别。
参考资料:特殊病征临床X线诊断学

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