英文药名：ELELYSO(taliglucerase alfa for injection)

中文药名：阿尔法冻干燥粉注射剂

生产厂家：美国辉瑞公司
药品介绍
Elelyso（taliglucerase alfa）已获美国FDA批准用于I型戈谢病（Gaucher disease，旧称高雪氏病）成年患者的长期治疗
批准日期：2012年5月2日 公司：辉瑞（Pfizer）公司
ELELYSO(taliglucerase alfa) 为皮下注射用
Initial US Approval: 2012
适应证和用途
ELELYSO™(taliglucerase alfa)为注射是一种溶酶体的水解葡萄糖脑苷脂专一酶适用于为成年确诊1型Gaucher病成年长期酶替代治疗(酶替代治疗)。
剂量和给药方法
（1）60 Units/kg每隔周给药静脉输注历时60-120分钟。
（2）当前正在用伊米苷酶[imiglucerase]治疗Gaucher氏病患者可转用ELELYSO。既往用稳定剂量伊米苷酶治疗患者建议用ELELYSO用当他们从伊米苷酶转至ELELYSO时相同剂量开始治疗.
（3）医生可根据达到和维持各患者治疗目标做剂量调整。临床试验曾评价剂量范围从11 Units/kg至73Units/kg每隔周。
剂型和规格
（1）为注射：用稀释液为配制的冰冻干燥粉。
（2）可达到单次使用小瓶内200 Unit

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ELELYSO safely and effectively. See full prescribing information for ELELYSO.
ELELYSO™ (taliglucerase alfa) for injection, for intravenous use
Initial U.S. Approval: 2012
RECENT MAJOR CHANGES
Indications and Usage (1) 8/2014
Dosage and Administration, Recommended Dosage (2.1)  8/2014
Dosage and Administration, Preparation Instructions (2.2) 8/2014
Dosage and Administration, Administration Instructions (2.3) 8/2014
Warnings and Precautions, Hypersensitivity Reactions Including Anaphylaxis (5.1) 8/2014
INDICATIONS AND USAGE
ELELYSO is a hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy (ERT) for adult and pediatric patients with a confirmed diagnosis of Type 1 Gaucher disease (1).
DOSAGE AND ADMINISTRATION
Treatment-naïve adult and pediatric patients 4 years of age and older: 60 units/kg administered every other week as a 60 to 120 minute intravenous infusion (2.1)
Patients switching from imiglucerase: Begin treatment with ELELYSO at the same unit/kg dose as the patient's previous imiglucerase dose. Physicians can make dosage adjustments based on achievement and maintenance of each patient's therapeutic goals (2.1).
DOSAGE FORMS AND STRENGTHS
For injection: lyophilized powder for reconstitution with diluent, 200 unit single-use vials (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions Including Anaphylaxis: Observe patients during and after the infusion; immediately discontinue infusion if anaphylaxis occurs and initiate appropriate treatment. Reduction in the infusion rate and/or pre-medication may prevent subsequent reactions (5.1, 6.3).
ADVERSE REACTIONS
The most commonly reported adverse reactions (≥5%) in clinical studies were pruritus, flushing, headache, arthralgia, pain in extremity, abdominal pain, vomiting, fatigue, back pain, dizziness, nausea and rash (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 8/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
ELELYSO is indicated for long-term enzyme replacement therapy (ERT) for adult and pediatric patients with a confirmed diagnosis of Type 1 Gaucher disease.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
Treatment-naïve patients: The recommended dosage for treatment-naïve adult and pediatric patients 4 years of age and older is 60 units per kg of body weight administered every other week as a 60 to 120 minute intravenous infusion.
Patients switching from imiglucerase: Patients currently being treated with imiglucerase for Type 1 Gaucher disease can be switched to ELELYSO. Patients previously treated on a stable dosage of imiglucerase are recommended to begin treatment with ELELYSO at that same dosage when they switch from imiglucerase to ELELYSO Dosage adjustments can be made based on achievement and maintenance of each patient's therapeutic goals [see Clinical Studies (14.2)].
ELELYSO should be reconstituted, diluted, and administered under the supervision of a healthcare professional.
2.2 Preparation Instructions
Each vial of ELELYSO provides 200 units of taliglucerase alfa and is intended for single use only. Do not use the vial more than one time. The reconstitution and dilution steps must be completed using aseptic technique.
ELELYSO should be reconstituted with Sterile Water for Injection and diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 mL to 200 mL, and delivered by intravenous infusion.
Prepare ELELYSO according to the following steps. Use aseptic technique.
a. Determine the number of vials to be reconstituted based on the patient's weight and the recommended dose of 60 units/kg, using the following calculations (1–3):
(1) Total dose in units = Patient's weight (kg) × dose (units/kg)
(2) Total number of vials = Total dose in units divided by 200 units/vial
(3) Round up to the next whole vial.
b. Remove the required number of vials from the refrigerator. Do not leave these vials at room temperature longer than 24 hours prior to reconstitution. Do not heat or microwave these vials.
c. Reconstitute each vial of ELELYSO with 5.1 mL of Sterile Water for Injection to yield a reconstituted product volume of 5.3 mL and a withdrawal volume of 5 mL. Upon reconstitution, mix vials gently. DO NOT SHAKE. Prior to further dilution, visually inspect the solution in the vials; the solution should be clear and colorless. Do not use if the solution is discolored or if foreign particulate matter is present.
d. Withdraw the calculated dose of drug from the appropriate number of vials and dilute with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 to 200 mL.
i. For pediatric patients, a final volume of 100 to 120 mL should be used.
ii.For adult patients, a final volume of 130 to 150 mL may be used. However, if the volume of reconstituted product alone is equal to or greater than 130 to 150 mL, then the final volume should not exceed 200 mL.
e. Mix gently. DO NOT SHAKE. Since this is a protein solution, slight flocculation (described as translucent fibers) occurs occasionally after dilution.
2.3 Administration Instructions
After reconstitution and dilution, the preparation should be administered via intravenous infusion and filtered through an in-line low protein-binding 0.2 μm filter.
For pediatric patients: An initial infusion rate of 1 mL/minute should be used. After tolerability to ELELYSO is established, the infusion rate may be increased, but should not exceed the maximum recommended infusion rate of 2 mL/minute. The total volume of the infusion should be delivered over a minimum of 60 minutes.
For adult patients: An initial infusion rate of 1.2 mL/minute should be used. After tolerability to ELELYSO is established, the infusion rate may be increased, but should not exceed the maximum recommended infusion rate of 2.2 mL/minute. The total volume of the infusion should be delivered over a minimum of 60 minutes.
As ELELYSO contains no preservative, the product should be used immediately once reconstituted. If immediate use is not possible, the reconstituted product may be stored for up to 24 hours at 2 to 8 °C (36 to 46 °F) under protection from light or up to 4 hours at 20 to 25 °C (68 to 77 °F) without protection from light. The diluted product may be stored for up to 24 hours at 2 to 8 °C (36 to 46 °F) under protection from light. Storage of the reconstituted product and the diluted product should not exceed a total of 24 hours. Do not freeze. Discard any unused product.
3 DOSAGE FORMS AND STRENGTHS
For injection: lyophilized powder for reconstitution; 200 units/vial.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions Including Anaphylaxis
Serious hypersensitivity reactions, including anaphylaxis, have occurred in some patients treated with ELELYSO. In clinical trials, 2 of 72 (2.8%) patients treated with ELELYSO experienced signs and symptoms consistent with anaphylaxis. Signs and symptoms of these patients included urticaria, hypotension, flushing, wheezing, chest tightness, nausea, vomiting, and dizziness. These reactions occurred during ELELYSO infusion.
In clinical trials with ELELYSO, 21 of 72 (29%) patients experienced hypersensitivity reactions, including anaphylaxis. Signs and symptoms of hypersensitivity reactions included pruritus, angioedema, flushing, erythema, rash, nausea, vomiting, cough, chest tightness, and throat irritation. These reactions have occurred up to 3 hours after the start of infusion [see Adverse Reactions (6.1)].
Due to the potential for anaphylaxis, appropriate medical support should be readily available when ELELYSO is administered. Observe patients closely for an appropriate period of time after administration of ELELYSO, taking into account the time to onset of anaphylaxis seen in clinical trials. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. If anaphylaxis occurs, ELELYSO should be immediately discontinued, and appropriate medical treatment should be initiated.
Management of hypersensitivity reactions should be based on the severity of the reaction and include slowing or temporary interruption of the infusion and/or administration of antihistamines, antipyretics, and/or corticosteroids for mild reactions. Pretreatment with antihistamines and/or corticosteroids may prevent subsequent hypersensitivity reactions. Patients were not routinely premedicated prior to infusion of ELELYSO during clinical studies. If severe hypersensitivity reactions occur, immediately stop the infusion of ELELYSO and initiate appropriate treatment.
Consider the risks and benefits of re-administering ELELYSO in patients who have experienced a severe reaction associated with ELELYSO. Caution should be exercised upon rechallenge, and appropriate medical support should be readily available [see Adverse Reactions (6.3)].
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In the clinical trials with ELELYSO, either as initial therapy or as therapy following a switch from imiglucerase (N=72), the most common (≥ 5%) adverse reactions included pruritus, flushing, headache, arthralgia, pain in extremity, abdominal pain, vomiting, fatigue, back pain, dizziness, nausea, and rash.
Clinical Trials of ELELYSO as Initial Therapy
Clinical Trial in Patients 19 Years and Older
The safety of ELELYSO at dosages of either 30 units/kg (n=16) or 60 units/kg (n=16) every other week was assessed in 32 adult treatment-naïve patients (aged 19 to 74 years) with Type 1 Gaucher disease in a 9-month randomized clinical trial.
Table 1: Adverse Reactions in ≥5% of Treatment-Naïve Adult Patients Treated with ELELYSO 

Preferred Term	Treatment-Naïve Adults (N=32) n (%)
Headache	6 (19%)
Arthralgia	4 (13%)
Fatigue	3 (9%)
Nausea	3 (9%)
Dizziness	3 (9%)
Abdominal pain	2 (6%)
Pruritus	2 (6%)
Flushing	2 (6%)
Vomiting	2 (6%)
Urticaria	2 (6%)

Similar adverse reactions were observed in patients who continued ELELYSO treatment during the extension trial for up to 24 months. One patient experienced a mild and intermittent Type III immune-mediated fixed drug eruption and continued in the study.
Clinical Trial in Patients 16 Years and Younger
The safety of ELELYSO at dosages of either 30 units/kg (n=4) or 60 units/kg (n=5) every other week was assessed in 9 pediatric treatment-naïve patients (aged 2 to 13 years) with Type 1 Gaucher disease in a 12-month randomized clinical trial.
The most common adverse reaction (≥10%) was vomiting, which occurred in 4 of 9 patients. Two patients developed hypersensitivity reactions; one patient experienced severe vomiting and gastrointestinal inflammation, and 1 experienced mild throat irritation and chest discomfort. Both patients responded to treatment with antihistamines and continued ELELYSO treatment.
Clinical Trial in Patients Switching from Imiglucerase Treatment to ELELYSO
The safety of ELELYSO was assessed in 31 patients (26 adult and 5 pediatric patients), ages 6 to 66 years old, with Type 1 Gaucher disease who had previously been receiving treatment with imiglucerase for a minimum of 2 years. ELELYSO was administered for 9 months at the same number of units as each patient's previous imiglucerase dose.
Table 2: Adverse Reactions in ≥10% of Patients Switched from Imiglucerase to ELELYSO

Preferred Term	Patients Switched from Imiglucerase (N=31; 26 adults and 5 children) n (%)
Arthralgia	4 (13%)
Headache	4 (13%)
Pain in extremity	3 (10%)

6.2 Immunogenicity
As with all therapeutic proteins, patients may develop anti-drug antibodies (ADA) to ELELYSO.
In clinical trials of treatment-naïve adults, 17 (53%) of 32 patients developed ADA during treatment with ELELYSO, and 2 (6%) of 32 patients tested positive for ADA at baseline prior to ELELYSO treatment. Of the 17 patients who developed ADA during ELELYSO treatment, 6 patients (35%) developed hypersensitivity reactions, 2 of whom met criteria for anaphylaxis. Two of the 17 patients who developed ADA during ELELYSO treatment discontinued treatment due to hypersensitivity reactions, one of whom had met criteria for anaphylaxis. Of the 2 patients who tested positive for ADA prior to initiation of ELELYSO treatment, one patient developed a hypersensitivity reaction during the first dose of ELELYSO and withdrew from the study. The second patient did not experience an adverse reaction.
In a clinical trial of treatment-naïve pediatric patients, 2 (22%) of 9 patients developed ADA during treatment with ELELYSO, and one of 9 patients was ADA-positive prior to initiation of ELELYSO. Two patients (1 who developed ADA during treatment and 1 who was ADA-positive at baseline) experienced hypersensitivity reactions. Both patients continued treatment with ELELYSO.
In a clinical trial of 31 patients (26 adult and 5 pediatric patients) who switched from imiglucerase to ELELYSO treatment, 4 adults (13% of patients) developed ADA during treatment with ELELYSO. Four additional patients (13%, 2 adults and 2 children) tested positive for ADA at baseline but became ADA-negative after the switch to ELELYSO. Two adult patients (1 patient who developed ADA after the switch and 1 who was ADA positive at baseline) experienced hypersensitivity reactions. Both patients continued treatment with ELELYSO.
The relationship between ADA and hypersensitivity reactions is not fully understood. Monitoring for ADA to ELELYSO may be useful in ADA positive patients or in patients who have experienced hypersensitivity reactions to ELELYSO or other enzyme replacement therapies.
Twenty-nine of the 30 adult and pediatric patients who tested positive for ADA were tested for neutralizing antibodies capable of inhibiting the enzymatic activity of ELELYSO. Neutralizing antibodies were detected in 3 (10.3%) of 29 patients, 2 treatment-naïve adult patients and 1 adult patient who switched from imiglucerase. Due to limited available data, it is not possible to determine a relationship between the presence of neutralizing antibodies and therapeutic response with ELELYSO.
Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to ELELYSO with the incidence of antibodies to other products may be misleading.
6.3 Postmarketing Experience
The following adverse reactions have been identified during post approval use of ELELYSO in countries where it is marketed. 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.
Immune system disorders: Anaphylaxis [see Warning and Precautions (5.1)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Category B
Risk Summary
There are no adequate and well-controlled studies of ELELYSO in pregnant women. In animal reproduction studies with taliglucerase alfa in pregnant rats at intravenous doses up to 5 times the recommended human dose (RHD) and in pregnant rabbits at intravenous doses up to 5 times the RHD, there was no evidence of harm to the fetus. Because animal reproduction studies are not always predictive of human response, ELELYSO should be used during pregnancy only if clearly needed.
Clinical Considerations
Disease-associated maternal and embryo-fetal risk
Women with Type 1 Gaucher disease have an increased risk of spontaneous abortion if disease symptoms are not treated and controlled pre-conception and during a pregnancy. Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations. Type 1 Gaucher disease manifestations may lead to adverse pregnancy outcomes, including hepatosplenomegaly which can interfere with the normal growth of a fetus and thrombocytopenia which can lead to increased bleeding and possible hemorrhage.
Animal Data
Reproduction studies have been performed with taliglucerase alfa administered during the period of organogenesis in rats and rabbits. In rats, intravenous doses up to 55 mg/kg/day (about 5 times the RHD of 60 units/kg based on the body surface area) did not cause any adverse effects on embryofetal development. In rabbits, intravenous doses up to 27.8 mg/kg/day (about 5 times the RHD of 60 units/kg based on the body surface area) did not show any embryofetal toxicity.
8.3 Nursing Mothers
It is not known whether ELELYSO is present in human milk. Because many drugs are present in human milk, caution should be exercised when ELELYSO is administered to a nursing woman.
8.4 Pediatric Use
The use of ELELYSO for treatment of pediatric patients with Type 1 Gaucher disease is supported by evidence of effectiveness from adequate and well-controlled trials of ELELYSO in adults, with additional pharmacodynamic data from 5 pediatric patients and pharmacokinetic data from 9 pediatric patients who participated in clinical trials [see Clinical Studies (14.1, 14.2), Clinical Pharmacology (12.3)]. Data from 14 pediatric patients were included in the safety evaluation [Adverse Reactions (6.1)]. There are insufficient data to inform dosing in patients less than 4 years of age.
Pediatric patients experienced a higher frequency of vomiting during ELELYSO treatment (4 of 9 treatment-naïve patients) than adult patients, and this may be a symptom of hypersensitivity reaction. The frequencies of other adverse reactions were similar between pediatric and adult patients [see Adverse Reactions (6.1)].
8.5 Geriatric Use
During clinical trials, 8 patients aged 65 or older were treated with ELELYSO. Clinical trials of ELELYSO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
11 DESCRIPTION
Taliglucerase alfa, a hydrolytic lysosomal glucocerebroside-specific enzyme for intravenous infusion, is a recombinant active form of the lysosomal enzyme, β-glucocerebrosidase, which is expressed in genetically modified carrot plant root cells cultured in a disposable bioreactor system (ProCellEx®). β-Glucocerebrosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide.
ELELYSO is produced by recombinant DNA technology using plant cell culture (carrot). Purified taliglucerase alfa is a monomeric glycoprotein containing 4 N-linked glycosylation sites (Mr = 60,800). Taliglucerase alfa differs from native human glucocerebrosidase by two amino acids at the N terminal and up to 7 amino acids at the C terminal. Taliglucerase alfa is a glycosylated protein with oligosaccharide chains at the glycosylation sites having terminal mannose sugars. These mannose-terminated oligosaccharide chains of taliglucerase alfa are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease.
ELELYSO is supplied as a sterile, non-pyrogenic, lyophilized product. The quantitative composition of each 200 Unit vial is D-mannitol (206.7 mg), polysorbate 80 (0.56 mg), sodium citrate (30.4 mg), and taliglucerase alfa (212 units). Citric acid may be added to adjust the pH at the time of manufacture.
A Unit is the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-β-D-glucopyranoside (pNP-Glc) per minute at 37°C. After reconstitution with Sterile Water for Injection, taliglucerase alfa concentration is 40 units/mL [see Dosage and Administration (2)]. Reconstituted solutions have a pH of approximately 6.0.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Gaucher disease is an autosomal recessive disorder caused by mutations in the human glucocerebrosidase gene, which results in a reduced activity of the lysosomal enzyme glucocerebrosidase. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency results in accumulation of substrate glucocerebroside primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells," which accumulate in the liver, spleen and bone marrow.
ELELYSO is a recombinant analog of human lysosomal glucocerebrosidase that catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, reducing the amount of accumulated glucocerebroside. ELELYSO uptake into cellular lysosomes is mediated by binding of ELELYSO mannose oligosaccharide chains to specific mannose receptors on the cell surface leading to internalization and subsequent transport to the lysosomes.
12.3 Pharmacokinetics
Pharmacokinetics of taliglucerase alfa were evaluated in 38 patients (29 adult and 9 pediatric patients) who received intravenous infusions of ELELYSO 30 units/kg or 60 units/kg every other week. ELELYSO 30 units/kg is not a recommended dose in treatment-naïve Gaucher disease patients [see Dosage and Administration (2.1)]. The pharmacokinetic parameters in adult and pediatric patients are summarized in Table 3.
In adult Type 1 Gaucher disease patients treated with ELELYSO 30 units/kg or 60 units/kg (N=29) every other week as initial therapy, pharmacokinetics were determined with the first dose and at Week 38 of treatment. The pharmacokinetics of taliglucerase alfa appeared to be nonlinear with a greater than dose-proportional increase in exposure at the doses studied.
No significant accumulation or change in taliglucerase alfa pharmacokinetics over time from Weeks 1 to 38 was observed with repeated dosages of 30 units/kg or 60 units/kg every other week.Based on the limited data, there were no significant pharmacokinetic differences between male and female patients in this study.
Pharmacokinetics of taliglucerase alfa were evaluated in 9 pediatric patients 4 to 17 years of age with Type 1 Gaucher disease who were treated with ELELYSO for 10 to 27 months. Six of the 9 patients were treatment-naïve, and 3 patients were switched from imiglucerase. In both the 30 units/kg and 60 units/kg dose groups, clearance values in pediatric patients were similar to those in adult patients. AUC values in pediatric patients were lower than AUC values in adult patients, due to weight-based dosing of taliglucerase alfa and lower body weights in pediatric patients.
Table 3: Taliglucerase Alfa Pharmacokinetic Parameters after Repeated Dosing in Adult and Pediatric Patients with Type 1 Gaucher Disease 

Pediatric Patients (N=9) Median (Range)		Adult Patients at Week 38 (N=29) Median (Range)
	30 units/kg n = 5	60 units/kg n = 4	30 units/kg n = 14	60 units/kg n = 15
Age (years)	15 (10, 17)	11 (4, 16)	35 (19, 74)	33 (19, 58)
Weight (kg)	44.3 (22.8, 71.0)	28.6 (16.5, 50.4)	72.5 (51.5, 99.5)	73.5 (58.5, 87.0)*
AUC0–∞ (ng*h/mL)	1416 (535, 1969)	2984 (1606, 4273)	2007 (1007, 10092)	6459 (2548, 21020)*
T1/2 (min)	37.1 (22.5, 56.8)	32.5 (18.0, 42.9)	18.9 (9.20, 57.9)	28.7 (11.3, 104)
CL (L/h)	30.5 (17.4, 37.8)	15.8 (11.7, 24.9)	30.5 (6.79, 68.0)	18.5 (6.20, 37.9)
Vss (L)	14.9 (10.1, 35.6)	8.80 (3.75, 21.4)	11.7 (2.3, 22.7)	10.7 (1.4, 18.5)

n = 14
Values were derived from concentration data expressed in ng/mL
13 NONCLINICAL TOXICOLOGY
13.1 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 taliglucerase alfa. In a male and female fertility study in rats, taliglucerase alfa did not cause any significant adverse effect on male or female fertility parameters up to a maximum dose of 55 mg/kg/day (about 5 times the recommended human dose of 60 units/kg based on the body surface area).
14 CLINICAL STUDIES
14.1 Clinical Trials of ELELYSO as Initial Therapy
Clinical Trial in Patients 19 Years and Older
The safety and efficacy of ELELYSO were assessed in 31 adult patients with Type 1 Gaucher disease. The trial was a 9-month, multi-center, double-blind, randomized trial in patients with Gaucher disease-related enlarged spleens (>8 times normal) and thrombocytopenia (<120,000 /mm3). Sixteen patients had enlarged livers and ten patients had anemia at baseline. All patients were naïve to ERT. Patients with severe neurological symptoms were excluded from the trial. Patients were 19 to 74 years of age (mean age 36 years), and 48% were male. Patients were randomized to receive ELELYSO at a dosage of either 30 units/kg (n=15) or 60 units/kg (n=16) every other week. The recommended dosage in treatment-naïve adult patients is 60 units/kg every other week. ELELYSO 30 units/kg every other week is not a recommended dosage [see Dosage and Administration (2.1)].
Table 4 shows the baseline values and mean (±SD) changes in clinical parameters (spleen volume, liver volume, platelet count, and hemoglobin) after 9 months of treatment with ELELYSO. For all clinical trials, liver and spleen volumes were measured by MRI and are reported as percentage of body weight (%BW) and multiples of normal (MN). The observed change from baseline in the primary endpoint, reduction in spleen volume, was considered to be clinically meaningful in light of the natural history of untreated Gaucher disease.
Table 4: Mean (SD) Changes in Clinical Parameters from Baseline to 9 Months in Treatment-Naïve Adults with Type 1 Gaucher Disease Initiating Therapy with ELELYSO (N=31) 

Clinical Parameter	30 units/kg (n=15) Mean (SD)	60 units/kg (n=16) Mean (SD)
Spleen Volume (%BW)	Baseline	3.1 (1.5)	3.3 (2.7)
	Month 9	2.2 (1.3)	2.1 (1.9)
	Change	-0.9 (0.4)	-1.3 (1.1)
Spleen Volume (MN)	Baseline	15.4 (7.7)	16.7 (13.4)
	Month 9	11.1 (6.3)	10.4 (9.4)
	Change	-4.5 (2.1)	-6.6.(5.4)
Liver Volume (%BW)	Baseline	4.2 (0.9)	3.8 (1.0)
	Month 9	3.6 (0.7)	3.1 (0.7)
	Change	-0.6 (0.5)	-0.6 (0.4)
Liver Volume (MN)	Baseline	1.7 (0.4)	1.5 (0.4)
	Month 9	1.4 (0.3)	1.2 (0.3)
	Change	-0.2 (0.2)	-0.3 (0.2)
Platelet Count (mm3)	Baseline	75,320 (40,861)	65,038 (28,668)
	Month 9	86,747 (50,989)	106,531 (53,212)
	Change	11,427 (20,214)	41,494 (47,063)
Hemoglobin (g/dl)	Baseline	12.2 (1.7)	11.4 (2.6)
	Month 9	14.0 (1.4)	13.6 (2.0)
	Change	1.6 (1.4)	2.2 (1.4)

The recommended ELELYSO dosage in treatment-naïve adult patients is 60 units/kg every other week. ELELYSO 30 units/kg every other week is not a recommended dosage. [see Dosage and Administration (2.1)]
Twenty-six of the 31 patients in this clinical trial continued blinded treatment with ELELYSO in an extension trial for a total treatment duration of 24 months. The following data are the changes in clinical parameters from baseline to Month 24 for the 30 units/kg (n=17) and 60 units/kg (n=14) dose groups, respectively: mean (SD) spleen volume (%BW) decreased -1.4 (0.6) and -2.0 (2.0); hemoglobin increased 1.3 (0.7) g/dL and 2.4 (2.3) g/dL; liver volume (%BW) decreased -1.1 (0.5) and -1.0 (0.7); and platelet count increased 28,433 (31,996) /mm3 and 72,029 (68,157) /mm3.
Clinical Trial in patients 16 years and younger
The safety and efficacy of ELELYSO were assessed in 9 pediatric patients with Type 1 Gaucher disease. The trial was a 12-month, multi-center, double-blind, randomized study in treatment-naïve patients. Patients were 2 to 13 years of age (mean age 8.1 years), and 67% were male. Patients were randomized to receive ELELYSO at a dosage of either 30 units/kg (n=4) or 60 units/kg (n=5) every other week. The recommended ELELYSO dosage in treatment-naïve pediatric patients is 60 units/kg every other week. ELELYSO 30 units/kg every other week is not a recommended dosage [see Dosage and Administration (2.1)].
Mean (±SD) baseline spleen volume for the 60 units/kg dose group was 29.4 (±24.3) MN, and decreased to 12.9 (±7.2) MN at 12 months. Baseline liver volume for the 60 units/kg dose group was 2.2 (±0.5) MN, and decreased to 1.7 (±0.3) MN at 12 months. Mean (±SD) platelet count for the 60 units/kg dose group was 99,600 (±42,899)/mm3 at baseline, and increased to 172,200 (±89,290)/mm3 at 12 months.
14.2 Clinical Trial in Patients Switching from Imiglucerase Treatment to ELELYSO
The safety and efficacy of ELELYSO were assessed in 31 patients (26 adult and 5 pediatric patients) with Type 1 Gaucher disease who were switched from imiglucerase to ELELYSO. The trial was a 9-month, multi-center, open-label, single arm study in patients who had been receiving treatment with imiglucerase at dosages ranging from 9.5 units/kg to 60 units/kg every other week for a minimum of 2 years. Patients were required to be clinically stable and have a stable biweekly dose of imiglucerase for at least 6 months prior to enrollment. Patients were 6 to 66 years of age (mean age 42 years, including pediatric patients), and 55% were male. Imiglucerase therapy was stopped, and treatment with ELELYSO was administered every other week at the same number of units as each patient's previous imiglucerase dose. If needed, adjustment of dosage was allowed during the study in order to maintain stability of clinical parameters (i.e., spleen volume, liver volume, platelet count, and hemoglobin).
Mean (±SD) organ volumes and hematologic values remained stable through 9 months of ELELYSO treatment. At baseline, spleen volume was 5.2 (±0.9) MN, liver volume was 1.0 (±0.1) MN, platelet count was 161,137 (±73,387)/mm3, and hemoglobin was 13.5 (±1.4) g/dL. After 9 months of ELELYSO treatment, spleen volume was 4.8 (±0.9) MN, liver volume was 1.0 (±0.0) MN, platelet count was 161,167 (±80,820)/mm3, and hemoglobin was 13.4 (±1.5) g/dL. ELELYSO dose remained unchanged in 30 of 31 patients. One patient required a dose increase at Week 24 (from 9.5 units/kg to 19 units/kg) for a platelet count of 92,000/mm3 at Week 22, which subsequently increased to 170,000/mm3 at Month 9.
16 HOW SUPPLIED/STORAGE AND HANDLING
ELELYSO is supplied as a lyophilized powder in single use vials. Each vial contains 200 units of ELELYSO.
NDC 0069-0106-01, 200 units per vial
Store ELELYSO under refrigeration at 2° C to 8° C (36° F to 46° F). Do not freeze. Protect vials from light.
As ELELYSO contains no preservative, the product should be used immediately once reconstituted. If immediate use is not possible, the reconstituted product may be stored for up to 24 hours at 2 to 8 °C (36 to 46 °F) under protection from light or up to 4 hours at 20 to 25 °C (68 to 77 °F) without protection from light. The diluted product may be stored for up to 24 hours at 2 to 8 °C (36 to 46 °F) under protection from light. Storage of the reconstituted product and the diluted product should not exceed a total of 24 hours. Do not freeze. Discard any unused product.
17 PATIENT COUNSELING INFORMATION
Hypersensitivity Reactions Including Anaphylaxis
Advise patients and caregivers that reactions related to administration and infusion may occur during and after ELELYSO treatment, including life-threatening anaphylaxis and severe hypersensitivity reactions. Inform patients of the signs and symptoms of anaphylaxis and hypersensitivity reactions, and have them seek medical care should signs and symptoms occur. Inform patients that they should be carefully re-evaluated for treatment with ELELYSO if serious hypersensitivity reactions, including anaphylaxis, occur. Reduction of the infusion rate and/or pre-treatment with antihistamines, antipyretics and/or corticosteroids may prevent subsequent reactions [see Warnings and Precautions (5.1)].
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa3cbd5d-677c-4b19-9032-d9182cb69a83

2012年，美国食品和药物管理局批准Elelyso（taliglucerase阿尔法）作为长期酶替代疗法治疗一类戈谢病（Gaucher disease，高雪病）—一种罕见的遗传疾病。
戈谢病发生在不能产生足够葡糖脑苷脂酶的人群中。这种酶缺乏导会致脂肪物质（脂类）在脾脏、肝脏、肾脏和其他器官中积聚。戈谢病的主要标志包括肝脏或脾脏受损、红细胞计数低（贫血）、血小板计数低和骨骼问题。
Elelyso是一种注射剂，对于确诊为1型（非神经型）戈谢病的患者，该药可以替代其所缺少的酶；Elelyso应当由专业医务人员隔周给药。在美国估计有6000千人罹患1型戈谢病。
“今天Elelyso获得了批准，这为1型戈谢病患者提供了一种新的替代疗法，”FDA药物评价与研究中心第三药物评价办公室主任、医学博士Julie Beitz说。“这也表明了FDA发展罕见病治疗的承诺。”
由于患者人数较少，所以2项临床试验总共纳入了56例1型戈谢病患者，评价了Elelyso的有效性。其中许多患者在一项长期延长研究中继续接受治疗。
一项多中心、双盲、平行剂量试验在31例未接受过酶替代疗法治疗的成年患者中评价了Elelyso作为初始治疗的有效性。患者随机接受剂量为30单位/kg或60单位/kg的Elelyso。
在这两种剂量上，Elelyso均有效地减少了脾脏体积——这项研究的主要终点——与基线时相比，接受30单位/kg Elelyso者脾脏体积平均减小29%，接受60单位/kg Elelyso者脾脏体积平均减小40%。试验还观察到肝脏体积、血小板计数、红细胞（血红蛋白）水平均有所改善。
另一项研究在25例从伊米苷酶（另一种酶替代疗法制品）转换为Elelyso治疗的1型戈谢病患者中评估了Elelyso的有效性。在这项多中心、开放标签、单组试验中，已接受伊米苷酶治疗至少两年的患者转换到相同剂量的Elelyso注射，隔周一次。结果表明，在9个月的评估期中，Elelyso可有效维持脾脏及肝脏体积、血小板计数和血红蛋白水平。
临床研究期间报告的最常见副作用是输液反应和过敏反应。输液反应的症状包括头痛、胸痛或胸部不适、乏力、疲劳，荨麻疹、皮肤发红、血压升高、背痛、关节痛和潮红。与其他静脉注射蛋白制品一样，研究也观察到一些患者在Elelyso输液期间出现了过敏反应。
Elelyso的其他常见副作用（在接受Elelyso治疗者中，发生率超过10%）包括上呼吸道感染、普通感冒样症状（鼻咽炎）、关节疼痛（关节痛）、流行性感冒、头痛、四肢疼痛、背痛和尿路感染。
Elelyso由总部位于纽约的辉瑞公司在Protalix生物治疗公司的许可下生产并销售。