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乳糖苷酶冻晶注射剂

 

Fabrazyme（Agalsidase beta）
制造商：健赞公司/赛诺菲-安万特
Fabrazyme是法布里（Fabry）病的酶替代治疗药物。法布里病是一种因半乳糖苷酶A缺乏导致的罕见的遗传性疾病，在临床上表现为脂肪在患者血管内多年累积，导致多器官功能障碍，使病人产生显著的疼痛并失能，最终引发器官衰竭和卒中。全球大约共有2200例患者。

Fabrazyme (法布瑞冻晶注射剂)
剂量：
16岁以上青少年及成人每两星期接受一次静脉输注液，剂量为1 mg/kg。起初20个星期，药品输注速率为0.25mg/min。输注时间不可少于2小时。 　　

相互作用：
不可与Chloroquine、Aminodatone、Benoquin、Gentamicin一起使用。 　　

注意事项：
对此药过敏、中等至严重的高血压(于输注时可能恶化)、肾衰竭(对于血浆肌酸酐大于2.5mg/dL患者的研究不足)及发烧病患(会恶化)应避免使用。监控治疗指标为定期测量血浆中GL-3浓度，正常浓度应低于1.2ng/ml。 　　

副作用：
发生频率大于10%的症状包括：全身性症状－寒颤、对温度变化敏感、发烧、四肢疼痛，呼吸系统－支气管痉挛、喉咙紧闷，胃肠道－恶心、呕吐，中枢及周围神经系统－头痛、震颤，心血管－四肢水肿、高血压，肌肉骨胳系统－肌痛

 

 

 

 

 

法布里病(Fabry  disease,又称酰基鞘氨醇己三糖苷酶缺乏症)是一种罕见的遗传性疾病。
法布里病患者的平均寿命为50岁。法布里（Fabry's）病为溶酶体α-半乳糖苷酶A缺乏症，由于N-脂酰鞘氨醇三已糖苷（globotriaosylceramide）及相关的糖鞘脂（glycosphingolipids）进行性积聚而引起，受累病人有肾脏、心脏和脑微血管病变，导致肾衰，中风，心脏并发症等疾病。

Fabrazyme是一种酶替代疗法。Genzyme在2000年向FDA提交新药申请。

该药是Genzyme公司生产的Fabrazyme，代替了病人体内缺乏的一种脂肪代谢酶，没有这种酶，器官内脂肪积聚得极多，引起心脏病发作、肾衰和疼痛。今天ＦＤＡ批准了Fabrazyme的两项特别内容：一是允许在得到它有效的完整证据前允许其销售，二是第一次批准就得到了7年的上市专有权，这是很少见的。

Fabrazyme是经基因工程制出的α-半乳糖苷酶A，在对58人的研究中，每两周静脉输液明显清除了三分之二病人肾脏和其它组织的脂肪积聚。"生活品质也有一定改善"，新泽西州42岁的马丁尼兹（Jaime Martinez）――他正在参加Fabrazyme的另一个研究――说，该药不能逆转肾脏损害，但他不再因为手脚那折磨人的疼痛而需要麻醉药了，也是他多年来第一次有足够的体力每个下午都能和孩子们玩耍。

Genzyme要证明Fabrazyme对病人最终是否有益的研究至少得在明年１月才能得到结果，但只要该公司尽快提供了确定资料，Fabrazyme可在几周内在美国开始销售，仍他们的女发言人拒绝透露价格（欧洲每年大约需180,000美元）。现在的问题是Genzyme公司是否能象政府要求的那样充分证实Fabrazyme的好处，它现正在进行一个比较该药与安慰剂的研究，许多不想接受安慰剂的参与者很可能要退出试验，但公司答应ＦＤＡ它们将通过一发现肾损害即将安慰剂转为药物的方法来努力留住足够的人参加研究。ＦＤＡ也打算允许一些新的统计分析方法来评估药物的利益，如比较病人用药前的病史等。这次试验对Genzyme公司甚为关键，它们同ＦＤＡ合作如何将决定其它药物也得到快速批准的难易。

ＦＤＡ的局长麦克利兰（Mark McClellan）说，希望通过定期清除脂肪沉积，该药能延迟或预防器官衰竭。"这可能是一种极为重要的药物"，他说，但"我想这一点非常清楚：批准后的有效性研究也是必要的"。Fabrazyme有一些严重的副作用，包括疼痛的输液反应和过敏反应。ＦＤＡ提醒卫生工作人员在病人输液时应仔细监测。

 

Fabrazyme

Generic Name: agalsidase beta
Dosage Form: injection, powder, lyophilized, for solution

 

 

 

Fabrazyme® (agalsidase beta) is indicated for use in patients with Fabry disease.  Fabrazyme reduces globotriaosylceramide (GL‑3) deposition in capillary endothelium of the kidney and certain other cell types.

SLIDESHOW

What's That? 10 of the Most Common Skin Conditions

The recommended dosage of Fabrazyme is 1 mg/kg body weight infused every two weeks as an intravenous (IV) infusion.  Patients should receive antipyretics prior to infusion [see Warnings and Precautions (5.2)].

The initial IV infusion rate should be no more than 0.25 mg/min (15 mg/hr).  The infusion rate may be slowed in the event of infusion reactions.  After patient tolerance to the infusion is well established, the infusion rate may be increased in increments of 0.05 to 0.08 mg/min (increments of 3 to 5 mg/hr) with each subsequent infusion.  For patients weighing < 30 kg, the maximum infusion rate should remain at 0.25 mg/min (15 mg/hr).  For patients weighing ≥ 30 kg, the administration duration should not be less than 1.5 hours (based on individual patient tolerability). 

Patients who have had a positive skin test to Fabrazyme or who have tested positive for anti-Fabrazyme IgE may be successfully re-challenged with Fabrazyme.  The initial re-challenge administration should be a low dose at a lower infusion rate, e.g., 1/2 the therapeutic dose (0.5 mg/kg) at 1/25 the initial standard recommended rate (0.01 mg/min).  Once a patient tolerates the infusion, the dose may be increased to reach the approved dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards (doubled every 30 minutes up to a maximum rate of 0.25 mg/min), as tolerated.

Fabrazyme does not contain any preservatives. Vials are for single use only. Discard any unused product.

Avoid shaking or agitating this product. Do not use filter needles during the preparation of the infusion.

Reconstitution and Dilution (using Aseptic Technique)

1.    Allow Fabrazyme vials and diluent to reach room temperature prior to reconstitution (approximately 30 minutes). The number of 35 mg and 5 mg vials needed is based on the patient’s body weight (kg) and the recommended dose of 1 mg/kg.

Select a combination of 35 mg and 5 mg vials so that the total number of mg is equal to or greater than the patient’s number of kg of body weight.

 

2.    Reconstitute each 35 mg vial of Fabrazyme by slowly injecting 7.2 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield a 5 mg/mL clear, colorless solution (total extractable amount per vial is 35 mg, 7 mL).

Reconstitute each 5 mg vial of Fabrazyme by slowly injecting 1.1 mL of Sterile Water for Injection, USP down the inside wall of each vial. Roll and tilt each vial gently. Each vial will yield a 5 mg/mL clear, colorless solution (total extractable amount per vial is 5 mg, 1 mL).

 

3.    Visually inspect the reconstituted vials for particulate matter and discoloration. Do not use the reconstituted solution if there is particulate matter or if it is discolored.

 

4.    The reconstituted solution should be further diluted with 0.9% Sodium Chloride Injection, USP to a total volume based on patient weight specified in Table 1 below. Prior to adding the volume of reconstituted Fabrazyme required for the patient dose, remove an equal volume of 0.9% Sodium Chloride Injection, USP from the infusion bag.

Table 1
Patient Weight (kg)	Minimum Total Volume (mL)
≤ 35	50
35.1 – 70	100
70.1 – 100	250
> 100	500

5.   

6.    Patient dose (in mg) ÷ 5 mg/mL = Number of mL of reconstituted Fabrazyme required for patient dose

7.   

8.    Example: Patient dose = 80 mg

9.    80 mg ÷ 5 mg/mL = 16 mL of Fabrazyme

10.  

11.   Slowly withdraw the reconstituted solution from each vial up to the total volume required for the patient dose. Inject the reconstituted Fabrazyme solution directly into the Sodium Chloride solution. Do not inject in the airspace within the infusion bag. Discard any vial with unused reconstituted solution.

12.    

13.   Gently invert infusion bag to mix the solution, avoiding vigorous shaking and agitation.

 

14.   Do not infuse Fabrazyme in the same intravenous line with other products.

 

15.   Administer Fabrazyme using an in-line low protein binding 0.2 µm filter.

Fabrazyme 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 Injection, USP for intravenous infusion.

Single-use vials are available in 35 mg and 5 mg dosages.

None.

Life-threatening anaphylactic and severe allergic reactions have been observed in patients during Fabrazyme infusions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. Interventions have included cardiopulmonary resuscitation, oxygen supplementation, IV fluids, hospitalization, and treatment with inhaled beta-adrenergic agonists, epinephrine, and IV corticosteroids.

In clinical trials and postmarketing safety experience with Fabrazyme, approximately 1% of patients developed anaphylactic or severe allergic reactions during Fabrazyme infusion. 

If anaphylactic or severe allergic reactions occur, immediately discontinue the administration of Fabrazyme and initiate necessary emergency treatment. Because of the potential for severe allergic reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

The risks and benefits of re-administering Fabrazyme following an anaphylactic or severe allergic reaction should be considered. Extreme care should be exercised, with appropriate medical support measures readily available, if the decision is made to re-administer the product [see Warnings and Precautions (5.4) and Clinical Studies (14)].

In clinical trials with Fabrazyme, approximately 50-55% of patients experienced infusion reactions during Fabrazyme administration, some of which were severe [see Warnings and Precautions (5.1)]. Severe infusion reactions experienced by more than one patient in clinical studies with Fabrazyme included chills, vomiting, hypotension, and paresthesia.  Other infusion reactions included pyrexia, feeling hot or cold, dyspnea, nausea, flushing, headache, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, urticaria, bradycardia, and somnolence. 

Most patients in clinical trials were pretreated with acetaminophen.  In patients experiencing infusion reactions, pretreatment with an antipyretic and antihistamine is recommended.  Infusion reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids.  Infusion reactions tended to decline in frequency with continued use of Fabrazyme.  However, infusion reactions may still occur despite extended duration of Fabrazyme treatment.  If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administrating additional antipyretics, antihistamines, and/or steroids may ameliorate the symptoms.  If severe infusion reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered, and appropriate medical treatment should be initiated.  Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated.  Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.  Patients who have experienced infusion reactions should be treated with caution when re-administering Fabrazyme. 

Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion reactions [see Warnings and Precautions (5.1) and (5.2)]. Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme.

In clinical trials with Fabrazyme, a few patients developed IgE antibodies or skin test reactivity specific to Fabrazyme.  Two of six patients in the re-challenge study discontinued treatment with Fabrazyme prematurely due to recurrent infusion reactions. Four serious infusion reactions occurred in three patients during Fabrazyme infusions, including bronchospasm, urticaria, hypotension, and development of Fabrazyme-specific antibodies.  Other infusion-related reactions occurring in more than one patient during the study included rigors, hypertension, nausea, vomiting, and pruritus.  Physicians should consider testing for IgE antibodies in patients who experienced suspected allergic reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies [see Warnings and Precautions (5.1) and Dosage and Administration (2)].

 

 

 

 

Patients who have had a positive skin test to Fabrazyme or who have tested positive for Fabrazyme-specific IgE antibody have been re-challenged with Fabrazyme using a re-challenge protocol [seeClinical Studies (14)].  Re-challenge of these patients should only occur under the direct supervision of qualified personnel, with appropriate medical support measures readily available.

There are no marketed tests for antibodies against Fabrazyme.  If testing is warranted, contact your local Genzyme representative or Genzyme Corporation at (800) 745-4447.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in patients in clinical practice.

The most serious adverse reactions reported with Fabrazyme treatment during clinical trials were anaphylactic and allergic reactions [see Warnings and Precautions (5.1)]. 

The most common adverse reactions reported with Fabrazyme are infusion reactions, some of which were severe [see Warnings and Precautions (5.1) and (5.2)].  Serious and/or frequently occurring (≥ 5% incidence) related adverse reactions consisted of one or more of the following: chills, pyrexia, feeling hot or cold, dyspnea, nausea, flushing, headache, vomiting, paresthesia, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, back pain, pallor, bradycardia, urticaria, hypotension, face edema, rash, and somnolence. The occurrence of somnolence can be attributed to clinical trial specified pretreatment with antihistamines.  Most infusion-related reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, and/or administration of antipyretics, antihistamines, or steroids.   

Other reported serious adverse events included stroke, pain, ataxia, bradycardia, cardiac arrhythmia, cardiac arrest, decreased cardiac output, vertigo, hypoacousia, and nephrotic syndrome.  These adverse events also occur as manifestations of Fabry disease; an alteration in frequency or severity cannot be determined from the small numbers of patients studied.

The data described below reflect exposure of 80 patients, ages 16 to 61 years, to 1 mg/kg Fabrazyme every two weeks in two separate double-blind, placebo-controlled clinical trials, for periods ranging from 1 to 35 months (mean 15.5 months).  All 58 patients enrolled in one of the two studies continued into an open-label extension study of Fabrazyme treatment for up to 54 additional months.  Patients were treated with antipyretics and antihistamines prior to the infusions.

Table 2 enumerates treatment-emergent adverse reactions (regardless of relationship) that occurred during the double-blind treatment periods of the two placebo-controlled trials (Study 1 and Study 2) [see Clinical Studies (14)].  Reported adverse reactions have been classified by Medical Dictionary for Regulatory Activities (MedDRA) terminology System Organ Class and Preferred Term.

Table 2 - Summary of Adverse Reactions (regardless of relationship) Occurring in Fabrazyme®-Treated Patients at an Incidence Greater than 2.5% Compared to Placebo-Treated Patients
MedDRA System Organ Class/ Preferred Term	Fabrazyme® n=80 (%)	Placebo n=60 (%)
Cardiac Disorders
Tachycardia	7 (9)	2 (3)
Ventricular wall thickening	4 (5)	1 (2)
Ear and Labyrinth Disorders
Tinnitus	6 (8)	2 (3)
Hypoacusis	4 (5)	0
Gastrointestinal Disorders
Toothache	5 (6)	2 (3)
Dry mouth	3 (4)	0
General Disorders and Administration Site Conditions
Chills	34 (43)	7 (12)
Pyrexia	31 (39)	13 (22)
Fatigue	19 (24)	10 (17)
Edema peripheral	17 (21)	4 (7)
Pain	13 (16)	8 (13)
Feeling cold	9 (11)	1 (2)
Adverse event	8 (10)	3 (5)
Chest discomfort	4 (5)	1 (2)
Infections and Infestations
Upper respiratory tract infection	35 (44)	18 (30)
Lower respiratory tract infection	14 (18)	4 (7)
Sinusitis	7 (9)	2 (3)
Pharyngitis	5 (6)	1 (2)
Fungal infection	4 (5)	0
Viral infection	4 (5)	0
Localized infection	3 (4)	0
Injury, Poisoning and Procedural Complications
Procedural pain	20 (25)	12 (20)
Post-procedural complication	8 (10)	1 (2)
Excoriation	7 (9)	1 (2)
Fall	5 (6)	2 (3)
Contusion	3 (4)	0
Thermal burn	3 (4)	0
Investigations
Blood creatinine increased	7 (9)	3 (5)
Musculoskeletal and Connective Tissue Disorders
Pain in extremity	15 (19)	5 (8)
Back pain	13 (16)	6 (10)
Myalgia	11 (14)	3 (5)
Muscle spasms	4 (5)	1 (2)
Nervous System Disorders
Headache	31 (39)	17 (28)
Paresthesia	25 (31)	11 (18)
Dizziness	17 (21)	5 (8)
Burning sensation	5 (6)	0
Psychiatric Disorders
Anxiety	5 (6)	2 (3)
Depression	5 (6)	1 (2)
Respiratory, Thoracic and Mediastinal Disorders
Cough	26 (33)	15 (25)
Nasal congestion	15 (19)	9 (15)
Dyspnea	6 (8)	1 (2)
Respiratory tract congestion	6 (8)	1 (2)
Wheezing	5 (6)	0
Skin and Subcutaneous Tissue Disorders
Rash	16 (20)	6 (10)
Pruritus	8 (10)	2 (3)
Vascular Disorders
Hypertension	11 (14)	3 (5)
Hot flush	4 (5)	0

Observed adverse reactions in the Phase 1/2 study and the open-label treatment period for the extension study following the controlled study were not different in nature or intensity. 

The safety profile of Fabrazyme in pediatric Fabry disease patients, ages 8 to 16 years, was found to be consistent with that seen in adults [see Use in Specific Populations (8.4) and Clinical Studies (14)].  The safety of Fabrazyme in patients younger than 8 years of age has not been evaluated.

Ninety-five of 121 (79%) adult patients and 11 of 16 (69%) pediatric patients (106 of 137, 74% of all patients) treated with Fabrazyme in clinical studies have developed IgG antibodies to Fabrazyme.  Most patients who develop IgG antibodies do so within the first three months of exposure.  IgG seroconversion in pediatric patients was associated with prolonged half-life of Fabrazyme, a phenomenon rarely observed in adult patients [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.4)].  A possible cause for this prolongation likely pertains to the ability of antibodies to act as “carriers” for their antigens.  Among the 14 female patients exposed to Fabrazyme in clinical studies, six (adult patients) developed IgG antibodies to Fabrazyme. 

IgG antibodies to Fabrazyme were purified from 15 patients with high antibody titers (≥ 12,800) and studied for inhibition of in vitro enzyme activity.  Under the conditions of this assay, most of these 15 patients had inhibition of in vitro enzyme activity ranging between 21-74% at one or more time points during the study.  Assessment of inhibition of enzyme uptake in cells has not been performed.  No general pattern was seen in individual patient reactivity over time.  The clinical significance of binding and/or inhibitory antibodies to Fabrazyme is not known.  In patients followed in the open-label extension study, reduction of GL-3 in plasma and GL-3 inclusions in superficial skin capillaries was maintained after antibody formation. 

As with all therapeutic proteins, there is potential for immunogenicity.  The data reflect the percentage of patients whose test results were considered positive for antibodies to Fabrazyme using an ELISA and radioimmunoprecipitation (RIP) assay for antibodies. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.  For these reasons, comparison of the incidence of antibodies to Fabrazyme with the incidence of antibodies to other products may be misleading.

Testing for IgE antibodies was performed in approximately 60 patients in clinical trials who experienced moderate to severe infusion reactions or in whom mast cell activation was suspected.  Seven of these patients tested positive for Fabrazyme-specific IgE antibodies or had a positive skin test to Fabrazyme.  Patients who have had a positive skin test to Fabrazyme, or who have tested positive for Fabrazyme-specific IgE antibodies in clinical trials with Fabrazyme have been re-challenged [see Clinical Studies (14), Warnings and Precautions (5.4) and Dosage and Administration (2)].

The following adverse reactions have been identified during post approval use of Fabrazyme. 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 agalsidase beta, severe and serious infusion-related reactions have been reported, some of which were life-threatening, including anaphylactic shock [see Warnings and Precautions (5.1)].  Reactions have included localized angioedema (including auricular swelling, eye swelling, dysphagia, lip swelling, edema, pharyngeal edema, face swelling, and swollen tongue), generalized urticaria, bronchospasm, and hypotension.

Adverse reactions (regardless of relationship) resulting in death reported in the postmarketing setting with Fabrazyme treatment included cardiorespiratory arrest, respiratory failure, cardiac failure, sepsis, cerebrovascular accident, myocardial infarction, renal failure, and pneumonia. Some of these reactions were reported in Fabry disease patients with significant underlying disease.

In addition to the adverse reactions reported in Adverse Reactions in Clinical Studies (6.1), the following adverse reactions have been reported during postmarketing use of agalsidase beta: arthralgia, asthenia, erythema, hyperhidrosis, infusion site reaction, lacrimation increased, leukocytoclastic vasculitis, lymphadenopathy, hypoesthesia, oral hypoesthesia, palpitations, rhinorrhea, oxygen saturation decreased, and hypoxia.

 

 

 

No drug interaction studies were performed.

No in vitro metabolism studies were performed.

There is no known interference by Fabrazyme with laboratory tests.  Antibody samples should be collected prior to Fabrazyme infusions.

Pregnancy Category B -

There are no adequate and well-controlled studies of Fabrazyme use in pregnant women. Reproduction studies performed in rats at doses up to 30 times the human dose have revealed no evidence of impaired fertility or negative effects on embryo fetal development due to Fabrazyme.  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 should be encouraged to enroll in the Fabry patient registry. The registry will monitor the effect of Fabrazyme on pregnant women and their offspring.  For more information, visit  www.fabryregistry.com or call (800) 745-4447 [see Patient Counseling Information (17)].

There is no information on the effect of Fabrazyme during labor and delivery. Pregnant females are encouraged to enroll in the Fabry registry [see Patient Counseling Information (17)].

It is not known whether Fabrazyme is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Fabrazyme is administered to a nursing woman.

Nursing mothers should be encouraged to enroll in the Fabry registry [see Use in Specific Populations (8.1) and Patient Counseling Information (17)].

The safety and efficacy of Fabrazyme were assessed in a multi-national, multi-center, uncontrolled, open-label study in 16 pediatric patients with Fabry disease (14 males, 2 females), ages 8 to 16 years [see Clinical Studies (14)].  Patients younger than 8 years of age were not included in clinical studies.  The safety and efficacy in patients younger than 8 years of age have not been evaluated.

Clinical studies of Fabrazyme did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Fabry disease is an X-linked genetic disorder. However, some heterozygous women will develop signs and symptoms of Fabry disease due to the variability of the X-chromosome inactivation within cells.

A total of 12 adult female patients with Fabry disease were enrolled in two separate randomized, double-blind, placebo-controlled clinical studies with Fabrazyme, and two female pediatric patients with Fabry disease, ages 11 years, were evaluated in an open-label, uncontrolled pediatric study [seeUse in Specific Populations (8.4) and Clinical Studies (14)].  Although the safety and efficacy data available in female patients in these clinical studies are limited, there is no indication that female patients respond differently to Fabrazyme compared to males.

There have been no reports of overdose with Fabrazyme. In clinical trials, patients received doses up to 3 mg/kg body weight.  The adverse reactions experienced by patients who received treatment with 3 mg/kg were similar to the adverse reactions experienced by patients who received treatment with 1 mg/kg.

Fabrazyme (agalsidase beta) is a recombinant human α-galactosidase A enzyme with the same amino acid sequence as the native enzyme. Purified agalsidase beta is a homodimeric glycoprotein with a molecular weight of approximately 100 kD. The mature protein is comprised of two subunits of 398 amino acids (approximately 51 kD), each of which contains three N-linked glycosylation sites. α‑galactosidase A catalyzes the hydrolysis of globotriaosylceramide (GL-3) and other α‑galactyl-terminated neutral glycosphingolipids, such as galabiosylceramide and blood group B substances to ceramide dihexoside and galactose. The specific activity of Fabrazyme is approximately 70 U/mg (one unit is defined as the amount of activity that results in the hydrolysis of 1 µmole of a synthetic substrate, p-nitrophenyl-α-D-galactopyranoside, per minute under the assay conditions).

Fabrazyme is produced by recombinant DNA technology in a Chinese Hamster Ovary mammalian cell expression system.

 

 

 

 

Fabrazyme is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder for reconstitution with Sterile Water for Injection, USP. Each 35 mg vial contains 37 mg of agalsidase beta, as well as 222 mg mannitol, 20.4 mg sodium phosphate monobasic monohydrate, and 59.2 mg sodium phosphate dibasic heptahydrate. Following reconstitution as directed, 35 mg of agalsidase beta (7 mL) may be extracted from each 35 mg vial.

Each 5 mg vial contains 5.5 mg of agalsidase beta, as well as 33.0 mg mannitol, 3.0 mg sodium phosphate monobasic monohydrate, and 8.8 mg sodium phosphate dibasic heptahydrate. Following reconstitution as directed, 5 mg of agalsidase beta (1 mL) may be extracted from each 5 mg vial.

Fabry disease is an X-linked genetic disorder of glycosphingolipid metabolism. Deficiency of the lysosomal enzyme α-galactosidase A leads to progressive accumulation of glycosphingolipids, predominantly GL-3, in many body tissues, starting early in life and continuing over decades. Clinical manifestations of Fabry disease include renal failure, cardiomyopathy, and cerebrovascular accidents. Accumulation of GL-3 in renal endothelial cells may play a role in renal failure.

Fabrazyme is intended to provide an exogenous source of α‑galactosidase A in Fabry disease patients. Nonclinical and clinical studies evaluating a limited number of cell types indicate that Fabrazyme will catalyze the hydrolysis of glycosphingolipids, including GL-3.

In a placebo-controlled study conducted in patients with Fabry disease after intravenous administration of 1 mg/kg of Fabrazyme every two weeks for 20 weeks, a reduction of GL-3 was observed in the capillary endothelium (vasculature) of kidney, heart and skin as determined by histological assessment, and in plasma as determined by ELISA [see Clinical Studies (14)].

Plasma pharmacokinetic profiles of Fabrazyme were characterized at 0.3, 1, and 3 mg/kg in adult patients with Fabry disease. The area under the plasma concentration-time curve (AUC∞) and the clearance (CL) did not increase proportionately with increasing doses, demonstrating that the enzyme follows non-linear pharmacokinetics (Table 3).  Plasma pharmacokinetic profiles were also characterized in adult patients with Fabry disease given 1 mg/kg Fabrazyme every 14 days for a total of 11 infusions.  Refer to Table 3 below for more details.

In 15 pediatric Fabry patients (ranging in age from 8 to 16 years old and weighing between 27.1 to 64.9 kg) who were dosed with 1 mg/kg every 14 days, Fabrazyme pharmacokinetics were not weight-dependent (Table 3).  Fabrazyme concentrations were about five times higher after IgG seroconversion, without any detectable impact on GL-3 clearance.

IgG seroconversion in pediatric patients was associated with prolonged half-life and plasma concentrations of Fabrazyme, a phenomenon rarely observed in adult patients. A possible cause for this prolongation likely pertains to the ability of antibodies to potentially act as “carriers” for their antigens [see Adverse Reactions (6.2) and Use in Specific Populations (8.4)].

Table 3 - Fabrazyme® Pharmacokinetic Summary
*   Vss = volume of distribution at steady state
Dose	Regimen	Mean Infusion Length (min)	Infusion number (n= patients)	AUC(0-∞) μg min/mL	Cmax μg/mL	Half-life min	CL mL/min/kg	Vss*   mL/kg
Study FB9702-01: Phase 1/2 Study in Adult Patients with Fabry Disease
0.3 mg/kg	q14 days x 5	132	1 (n=3)	79 ± 24	0.6 ± 0.2	92 ± 27	4.1 ± 1.2	225 ± 62
		128	5 (n=3)	74 ± 30	0.6 ± 0.2	78 ± 67	4.6 ± 2.2	330 ± 231
1 mg/kg	q14 days x 5	115	1 (n=3)	496 ± 137	5.0 ± 1.1	67 ± 12	2.1 ± 0.7	112 ± 13
		120	5 (n=2)	466 ± 382	4.74 ± 4.3	45 ± 3	3.2 ± 2.6	243 ± 236
3 mg/kg	q14 days x 5	129	1 (n=2)	4168 ± 1401	29.7 ± 14.6	102 ± 4	0.8 ± 0.3	81 ± 45
		300	5 (n=2)	4327 ± 2074	19.8 ± 5.8	87 ± 21	0.8 ± 0.4	165 ± 80
Study AGAL-1-002-98: Phase 3 Study in Adult Patients with Fabry Disease
1 mg/kg	q14 days x 11	280	1-3 (n=11)	649 ± 226	3.5 ± 1.6	89 ± 20	1.8 ± 0.8	120 ± 80
		280	7 (n=11)	372 ± 223	2.1 ± 1.14	82 ± 25	4.9 ± 5.6	570 ± 710
		300	11 (n=11)	784 ± 521	3.5 ± 2.2	119 ± 49	2.3 ± 2.2	280 ± 230
Study AGAL-016-01: Phase 2 Study in Pediatric Patients with Fabry Disease
1 mg/kg	q14 days x 24	208	1 (n=8-9)	344 ± 307	2.2 ± 1.9	86 ± 27	5.8 ± 4.6	1097 ± 912
		111	12 (n=15)	1007 ± 688	4.9 ± 2.4	130 ± 41	1.6 ± 1.2	292 ± 185
		108	24 (n=9-10)	1238 ± 547	7.1 ± 4.4	151 ± 59	1.1 ± 0.8	247 ± 146
All data reported as the mean ± standard deviation.

 

 

 

 

 

There are no animal or human studies to assess the carcinogenic or mutagenic potential of Fabrazyme. There are no studies assessing the potential effect of Fabrazyme on fertility in humans.

The safety and efficacy of Fabrazyme were assessed in four clinical studies in patients with Fabry disease.

Study 1 was a randomized, double-blind, placebo-controlled, multi-national, multi-center study of 58 Fabry patients (56 males and 2 females), ages 16 to 61 years, all naïve to enzyme replacement therapy.  Patients received either 1 mg/kg of Fabrazyme or placebo every two weeks for five months (20 weeks) for a total of 11 infusions.  All patients were pretreated with acetaminophen and an antihistamine to decrease or prevent infusion reactions.  Oral steroids were an additional option to the pretreatment regimen for patients who exhibited severe or recurrent infusion reactions.  The primary efficacy endpoint of GL-3 inclusions in renal interstitial capillary endothelial cells, was assessed by light microscopy and was graded on an inclusion severity score ranging from 0 (normal or near normal) to 3 (severe inclusions).

A GL-3 inclusion score of 0 was achieved in 20 of 29 (69%) patients treated with Fabrazyme compared to 0 of 29 treated with placebo (p<0.001).  Similar reductions in GL-3 inclusions were observed in the capillary endothelium of the heart and skin (Table 4).  No differences between groups in symptoms or renal function were observed during this five-month study.

Table 4 - Reduction of GL-3 Inclusions toNormalor NearNormalLevels (0 Score) in the Capillary Endothelium of the Kidney, Heart, and Skin
*   Results reported where biopsies were available
	5 Months of the Controlled Study		6 Months of the Open-label Extension Study
	Placebo (n=29)	Fabrazyme® (n=29)	Placebo/ Fabrazyme® (n=29)*	Fabrazyme® / Fabrazyme® (n=29)*
Kidney	0/29	20/29	24/24	23/25
Heart	1/29	21/29	13/18	19/22
Skin	1/29	29/29	25/26	26/27

All 58 patients in Study 1 participated in an open-label extension study of Fabrazyme at 1 mg/kg every two weeks, which continued for an additional 54 months.  At the end of six months of open-label treatment, most patients achieved a GL-3 inclusion score of 0 in capillary endothelium (Table 4).  GL-3 was decreased to normal or near normal levels in mesangial cells, glomerular capillary endothelium, interstitial cells, and non-capillary endothelium.  GL-3 deposition was still present in vascular smooth muscle cells, tubular epithelium and podocytes, at variably reduced levels.  Forty-four of the 58 patients completed 54 months of the open-label extension study.  Thirty-six of these 44 patients underwent follow-up skin biopsy, and 31 of these patients showed sustained GL-3 clearance in the capillary endothelium of the skin.  Follow-up heart and kidney biopsies were assessed in only 8 of the 44 patients, which showed sustained GL-3 clearance in the capillary endothelium of the kidney in 8 patients, and sustained GL-3 clearance in the capillary endothelium of the heart in 6 patients.  Plasma GL-3 levels were reduced to normal levels (≤ 7.03 µg/mL determined by LC/MS/MS) and remained at normal levels after up to 60 months of treatment.  The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.

Study 2 was a randomized (2:1 Fabrazyme to placebo), double-blind, placebo-controlled, multi-national, multi-center study of 82 patients (72 males and 10 females), ages 20 to 72 years, all naïve to enzyme replacement therapy.  Patients received either 1 mg/kg of Fabrazyme or placebo every two weeks for up to a maximum of 35 months (median 18.5 months).  There was significant difference in post-baseline plasma GL-3 levels in the Fabrazyme-treated patients compared to placebo.  The reduction in plasma GL-3 levels in the Fabrazyme group compared to the placebo group was significant at one year (p<0.0001) and at two years (p=0.0019).  Fourteen patients (8 in Fabrazyme-treated and 6 in placebo) had skin biopsies at first infusion and final visit.  All Fabrazyme-treated patients had capillary endothelium and deep vessel endothelium scores of zero at the final visit.  Four (4) of 6 placebo patients had non-zero capillary endothelium scores (p=0.0150), and 6 of 6 had non-zero deep vessel endothelium scores (p=0.0003).

Sixty-seven patients who participated in Study 2 were subsequently entered into an open-label extension study in which all patients received 1 mg/kg of Fabrazyme every two weeks for up to a maximum of 18 months.  There was a statistically significant reduction in mean plasma GL-3 levels with durability in effect through the additional 18 months of treatment in the extension study from pretreatment baseline.

Study 3 (Pediatric Study) was an open-label, uncontrolled, multi-national, multi-center study to evaluate safety, pharmacokinetics, and pharmacodynamics of Fabrazyme treatment in 16 pediatric patients with Fabry disease (14 males, 2 females), who were ages 8 to 16 years at first treatment.  All patients received Fabrazyme 1 mg/kg every two weeks for up to 48 weeks.  At baseline, all 14 males had elevated plasma GL-3 levels (i.e., > 7.03 µg/mL), whereas the two female patients had normal plasma GL-3 levels.  Twelve of the 14 male patients, and no female patients, had GL-3 inclusions observed in the capillary endothelium on skin biopsies at baseline.  At Weeks 24 and 48 of treatment, all 14 males had plasma GL-3 within the normal range.  The 12 male patients with GL-3 inclusions in capillary endothelium at baseline achieved GL-3 inclusion scores of 0 at Weeks 24 and 48 of treatment.  The two female patients’ plasma GL-3 levels remained normal through study Week 48.

 

 

 

 

 

 

 

 

 

 

No new safety concerns were identified in pediatric patients in this study, and the overall safety and efficacy profile of Fabrazyme treatment in pediatric patients was found to be consistent with that seen in adults.  Immunologic responses in pediatric patients may differ from those in adults, as IgG seroconversion in pediatric patients was associated with prolonged half-life concentrations of Fabrazyme, a phenomenon rarely observed in adult patients [see Clinical Pharmacology (12.3), Adverse Reactions (6.2), and Use in Specific Populations (8.4)].

Study 4 was an open-label, re-challenge study to evaluate the safety of Fabrazyme treatment in patients who had a positive skin test to Fabrazyme or who had tested positive for Fabrazyme-specific IgE antibodies.  In this study, six adult male patients, who had experienced multiple or recurrent infusion reactions during previous clinical trials with Fabrazyme, were re-challenged with Fabrazyme administered as a graded infusion, for up to 52 weeks of treatment [see Warnings and Precautions (5.4)].  The initial two re-challenge doses of Fabrazyme were administered as a 0.5 mg/kg dose per week at an initial infusion rate of 0.01 mg/min for the first 30 minutes (1/25th the usually recommended maximum infusion rate).  The infusion rate was doubled every 30 minutes thereafter, as tolerated, for the remainder of the infusion up to a maximum rate of 0.25 mg/min.  If the patient tolerated the infusion, the dose was increased to 1 mg/kg every two weeks (usually recommended dose), and the infusion rate was increased by slow titration upwards [see Dosage and Administration (2)].  Four of the six patients treated in this study received at least 26 weeks of study medication, and two patients discontinued prematurely due to recurrent infusion reactions [see Warnings and Precautions (5.4)].

Fabrazyme is supplied as a sterile, nonpyrogenic, white to off-white lyophilized cake or powder. Fabrazyme 35 mg vials are 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 purple flip-off cap. Fabrazyme 5 mg vials are supplied in single-use, clear Type I glass 5 mL (cc) vials. The closure consists of a siliconized butyl stopper and an aluminum seal with a plastic gray flip-off cap.

35 mg vial: NDC 58468-0040-1

5 mg vial: NDC 58468-0041-1

Refrigerate vials of Fabrazyme at 2° to 8°C (36° to 46°F).  DO NOT USE Fabrazyme after the expiration date on the vial.  Reconstituted and diluted solutions of Fabrazyme should be used immediately.  This product contains no preservatives.  If immediate use is not possible, the reconstituted and diluted solution may be stored for up to 24 hours at 2° to 8°C (36° to 46°F).

Patients should be informed that a Registry has been established in order to better understand the variability and progression of Fabry disease in the population as a whole and in women [see Use in Specific Populations (8.6)], and to monitor and evaluate long-term treatment effects of Fabrazyme. The Registry will also monitor the effect of Fabrazyme on pregnant women and their offspring. Patients should be encouraged to participate and advised that their participation is voluntary and may involve long-term follow-up. For more information, visit www.fabryregistry.com or call (800) 745-4447.

Fabrazyme is manufactured and distributed by:
Genzyme Corporation
500 Kendall Street
Cambridge,MA02142
1-800-745-4447 (phone)

U.S.License Number: 1596

Fabrazyme and Genzyme are registered trademarks of Genzyme Corporation.

Package Carton – Principal Display Panel – 35 mg Carton

Package contains one vial of

Fabrazyme®

agalsidase beta 

35mg

Store Refrigerated At 2-8°C (36-46°F)

Do Not Freeze or Shake

Contains No Preservatives

For Single Use Only

NoU.S.Standard of Potency

See package insert for

dosage and administration.

 

 

 

 

Package Carton – Principal Display Panel – 5 mg Carton

Package contains one vial of

Fabrazyme®
agalsidase beta 

5mg

Store Refrigerated At 2-8°C (36-46°F)
Do Not Freeze or Shake

Contains No Preservatives

For Single Use Only

NoU.S.Standard of Potency

See package insert for
dosage and administration.

Fabrazyme® is a registered
trademark of Genzyme Corporation.

Fabrazyme agalsidase beta injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:58468-0041 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AGALSIDASE BETA (AGALSIDASE BETA) AGALSIDASE BETA 5 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength MANNITOL   SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE   SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE

Packaging # Item Code Package Description   1 NDC:58468-0041-1 1 mL in 1.0 VIAL, GLASS

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103979 12/17/2008

Fabrazyme agalsidase beta injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:58468-0040 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AGALSIDASE BETA (AGALSIDASE BETA) AGALSIDASE BETA 5 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength MANNITOL   SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE   SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE

Packaging # Item Code Package Description   1 NDC:58468-0040-1 1 mL in 1.0 VIAL, GLASS

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA103979 12/17/2008

Labeler - Genzyme Corporation (025322157)
Establishment
Name	Address	ID/FEI	Operations
Genzyme Corporation		926029653	API MANUFACTURE(58468-0040, 58468-0041)

Establishment
Name	Address		ID/FEI	Operations
Genzyme Corporation			968278916	API MANUFACTURE(58468-0040, 58468-0041)
Establishment
Name		Address	ID/FEI	Operations
Genzyme Corporation			050424395	LABEL(58468-0040, 58468-0041)

Establishment
Name	Address		ID/FEI	Operations
Hospira, Inc.			030606222	MANUFACTURE(58468-0040, 58468-0041)
Establishment
Name		Address	ID/FEI	Operations
Genzyme Corporation			968278874	API MANUFACTURE(58468-0040, 58468-0041)

Establishment
Name	Address	ID/FEI	Operations
Genzyme Corporation		968278932	API MANUFACTURE(58468-0040, 58468-0041)
Establishment
Name	Address	ID/FEI	Operations
Genzyme Corporation		943130096	API MANUFACTURE(58468-0040, 58468-0041)

Establishment
Name	Address	ID/FEI	Operations
Genzyme Corporation		034378252	ANALYSIS(58468-0040, 58468-0041)
Establishment
Name	Address	ID/FEI	Operations
Genzyme Corporation		968302658	ANALYSIS(58468-0040, 58468-0041)

Establishment
Name	Address	ID/FEI	Operations
BioReliance		175174176	ANALYSIS(58468-0040, 58468-0041)
Establishment
Name	Address	ID/FEI	Operations
BioReliance		505004556	ANALYSIS(58468-0040, 58468-0041)

Establishment
Name	Address	ID/FEI	Operations
Bionique Testing Laboratories		108684523	ANALYSIS(58468-0040, 58468-0041)

Revised: 12/2012

 

Genzyme Corporation