药品简介

拉布立酶(rasburicase).Sanofi-Synthelabo 公司生产的重组尿酸氧化酶Rasburicase为冻干粉针制剂,商品名为Fasturtec® ，Elitek®, 该药于2001年在欧洲以Fasturtec®的商品名被批准上市，现已在整个欧洲和美国上市，在美国以Elitek®的名称于2002年7月被批准上市，用于预防和治疗因治疗血癌所引起的高尿酸血症。 
【药物别名】 Fasturtec 

【药理毒理】（法）Sanofi-Synthelabo公司开发，2001年6月在德国和英国首次上市。
高尿酸血症是白血病和淋巴瘤及其治疗的一种常见并发症。对于骨髓增生性疾病或造血系统恶性肿瘤病人，核酸的分解代谢是恶性细胞群增加更新的结果，从而增加嘌呤的代谢，导致尿酸血浓度的增高。癌症的积极治疗方案可引起细胞溶解增多和嘌呤代谢物的释放。肿瘤溶解综合征的特征为严重高尿酸血症、高磷酸盐血症、高钾血症、高钙血症和急性肾衰。作为高尿酸血症的结果，当尿中的尿酸达到过饱和，肾小管和远端收集系统出现尿酸结晶会引起肾功能不全。 尽管控制代谢异常可降低急性肾衰的危险性，然而，在开始治疗后，晚期伯基特淋巴瘤和B细胞急性淋巴细胞白血病患儿25%仍会出现急性肾衰。 高尿酸血症的标准预防或治疗方案为使用别嘌醇（allopurinol）治疗，进行尿液碱化，水合和渗透性利尿。别嘌醇通过抑制黄嘌噙氧化酶阻滞尿酸形成，但会增加肾脏排泄尿酸前体（次黄嘌呤和黄嘌呤）的负荷。与次黄嘌呤不同，黄嘌呤在尿中比尿酸难溶。有时别嘌醇治疗的病人也可出现黄嘌呤肾病和结石。此外，对于病人体内存留的尿酸的排泄，使用别嘌醇治疗无效。 本品为由来自曲霉菌DNA克隆的酿酒酿母（Saccharomyces cerevisae）基因工程突变株产生的重组尿酸氧化酶。尿酸氧化酶可催化尿酸的氧化，形成尿囊素，后者为一种比较容易排泄的代谢物，其溶解度为尿酸的5～10倍。大多数哺乳动物体内均有内源性尿酸氧化酶，但人体则缺乏这种酶。
法国Sanofi Synthelabo公司生产的非重组尿酸氧化酶，由黄曲霉培养液纯化而得，治疗高尿酸血症疗效较别嘌醇显著。然而，非重组产品发生急性过敏反应（如支气管痉挛，低氧血症）者约为5%，包括以往无过敏史的病人或罹患高铁血红蛋白血症和6-磷酸葡萄糖脱氢酶（G-6-PD）缺乏的溶血性贫血病人。 

【药 动 学】输注本品一日0.2mg/kg，约2～3天可达到稳态血药浓度，消除半衰期约为19小时，儿童和青少年较成年人的本品清除率高。肾或肝功能不全病人无需进行剂量调整。本品开始输注后24小时内呆使尿酸浓度降至2～3mg/dl以下。高尿酸血症病人使用本品治疗4小时，尿酸水平达到正常，而使用别嘌醇则需要24小时才能达到正常。给药期间一般可保持低尿酸水平，此外，在进行化疗时或化疗后，可能会出现一过性尿酸升高。 
本品为由经基因工程改造的酿酒酿母株产生的重组尿酸氧化酶。分子量约为34kDa。在血液学肿瘤病人化疗初期使用本品可预防和治疗高尿酸血症，进而预防急性肾衰。
本品应在化疗前或化疗早期使用。目前尚缺乏有关联合治疗的资料。 

【适 应 症】本品为重组尿酸氧化酶，可用于治疗和预防具有高危肿瘤溶解综合征的血液恶性肿瘤病人的急性高尿酸血症，尤其适用于化疗引起的高尿酸血症病人。 

【不良反应】使用本品可能出现的常见不良反应有发热，恶心，呕吐和皮疹。发生率分别为6.8%，1.7%,1.4%和1.4%。腹泻（0.9%），头痛0.9%,过敏(0.6%)等较少见。 

【用法用量】本品推荐剂量为一日0.20mg/kg，于30分钟内静脉滴注。用药时加至50ml的9mg/ml氯化钠溶液（0.9% w/v)中。本品治疗时间一般为5～7天。 本品用药不影响化疗药物的用药时间和化疗方案。但输注本品的输注管不应与输注化疗药物的同用，以预防可能的药的间的不相容性。如不能使用不同的输液管，则应在输注化疗药物和本品之间使用氯化钠溶液洗净。 

【注意事项】本品禁用于对尿酸氧化酶或辅料过敏者。G-6-PD缺乏以及其他细胞代谢异常者易出现贫血，故也禁用本品。尚无有关本品对孕妇影响的资料，也未见有关动物试验报道。本品不宜用于孕妇和哺乳期妇女。有特应性变态反应史病人慎用本品。 尚未见有关本品的代谢研究，但认为本品与其他药物未必会发生相互作用。 
本品为一种蛋白质，因而可能诱导抗体产生。再次给药后可能增加过敏反应或使临床作用受到限制。但大多数病人在接受一个疗程本品治疗后，在以后的化疗中可以换用别嘌醇。Piu等在121例病人中检测到14%病人出现抗体，但Goldman等在23例病人中进行的研究则未见病人出现抗体。

 Pronunciation

(ras BYOOR i kayse)

Index Terms

Recombinant Urate OxidaseUrate Oxidase

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Elitek: 1.5 mg (1 ea); 7.5 mg (1 ea)

Brand Names: U.S.

Elitek

Pharmacologic Category

EnzymeEnzyme, Urate-Oxidase (Recombinant)

Pharmacology

Rasburicase is a recombinant urate-oxidase enzyme, which converts uric acid to allantoin (an inactive and soluble metabolite of uric acid); it does not inhibit the formation of uric acid.

Distribution

Pediatric patients: 110 to 127 mL/kg; Adults: 76 to 138 mL/kg

Onset of Action

Uric acid levels decrease within 4 hours of initial administration

Half-Life Elimination

~16 to 23 hours

Special Populations: Race

The geometric mean values of body weight-normalized clearance were approximately 40% lower in Japanese than in Caucasian patients.

Use: Labeled Indications

Hyperuricemia associated with malignancy: Initial management of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies receiving chemotherapy expected to result in tumor lysis and elevation of plasma uric acid

Limitations of use: Indicated only for a single course of treatment

Contraindications

History of anaphylaxis or severe hypersensitivity to rasburicase or any component of the formulation; history of hemolytic reaction or methemoglobinemia associated with rasburicase; glucose-6-phosphatase dehydrogenase (G6PD) deficiency

Dosing: Adult

Hyperuricemia associated with malignancy: IV: 0.2 mg/kg once daily for up to 5 days (use beyond 5 days or administration of more than 1 course is not recommended) or

Alternate dosing (off-label; Coiffier 2008): 0.05 to 0.2 mg/kg once daily for 1 to 7 days (average of 2 to 3 days) with the duration of treatment dependent on plasma uric acid levels and clinical judgment (patients with significant tumor burden may require an increase to twice daily); the following dose levels are recommended based on risk of tumor lysis syndrome (TLS):

High risk: 0.2 mg/kg once daily (duration is based on plasma uric acid levels)

Intermediate risk: 0.15 mg/kg once daily (duration is based on plasma uric acid levels)

Low risk: 0.1 mg/kg once daily (duration is based on clinical judgment); a dose of 0.05 mg/kg was used effectively in one trial

Single-dose rasburicase (off-label dosing; based on limited data): 0.15 mg/kg (Campara 2009; Liu 2005) or 3 to 7.5 mg as a single dose (Hutcherson 2006; McBride 2013; McDonnell 2006; Reeves 2008; Trifilio 2006); repeat doses (1.5 to 6 mg) may be needed based on serum uric acid levels

Prevention in high-risk patients with hematologic malignancies (off-label dosing): 3 mg as a single dose (Jones 2015)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hyperuricemia associated with malignancy: IV: 0.2 mg/kg once daily for up to 5 days (use beyond 5 days or administration of more than 1 course is not recommended) or

Alternate dosing (off-label; Coiffier 2008): 0.05 to 0.2 mg/kg once daily for 1 to 7 days (average of 2 to 3 days) with the duration of treatment dependent on plasma uric acid levels and clinical judgment (patients with significant tumor burden may require an increase to twice daily); the following dose levels are recommended based on risk of tumor lysis syndrome (TLS):

High risk: 0.2 mg/kg once daily (duration is based on plasma uric acid levels)

Intermediate risk: 0.15 mg/kg once daily (duration is based on plasma uric acid levels); may consider managing initially with a single dose

Low risk: 0.1 mg/kg once daily (duration is based on clinical judgment); a dose of 0.05 mg/kg was used effectively in one trial

Single-dose rasburicase (off-label dosing; based on limited data): 0.15 mg/kg; additional doses may be needed based on serum uric acid levels (Liu 2005)

Prevention in high-risk patients with hematologic malignancies (off-label dosing): 0.2 mg/kg as a single dose (Jones 2015)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Reconstitution

Reconstitute with provided diluent (use 1 mL diluent for the 1.5 mg vial and 5 mL diluent for the 7.5 mg vial). Mix by gently swirling; do not shake or vortex. Discard if discolored or containing particulate matter. Total dose should be further diluted in NS to a final volume of 50 mL. Because the provided diluent is in a glass ampule, the diluent should be filtered prior to adding to the rasburicase vial for reconstitution (ISMP [Smetzer 2017]).

Administration

IV infusion over 30 minutes; do not administer as a bolus. Do not filter during infusion. If not possible to administer through a separate line, IV line should be flushed with at least 15 mL saline prior to and following rasburicase infusion.

The optimal timing of rasburicase administration (with respect to chemotherapy administration) is not specified in the manufacturer's labeling. In some studies, chemotherapy was administered 4 to 24 hours after the first rasburicase dose (Cortes 2010; Kikuchi 2009; Vadhan-Raj 2012); however, rasburicase generally may be administered irrespective of chemotherapy timing.

Storage

The lyophilized drug product and the diluent for reconstitution should be stored at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Reconstituted solution and solution diluted for infusion may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F). Discard unused product.

Drug Interactions

There are no known significant interactions.

Test Interactions

Specific handling procedures must be followed to prevent the degradation of uric acid in plasma samples. Blood must be collected in prechilled tubes containing heparin anticoagulant. Samples must then be immediately immersed and maintained in an ice water bath. Prepare samples by centrifugation in a precooled centrifuge (4°C). Samples must be analyzed within 4 hours of collection.

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (50%)

Central nervous system: Headache (26%), anxiety (24%)

Dermatologic: Rash (13%; serious: <1%)

Endocrine & metabolic: Hypophosphatemia (17%), hypervolemia (12%)

Gastrointestinal: Nausea (27% to 58%), vomiting (38% to 50%), abdominal pain (20% to 22%), constipation (20%), diarrhea (20%), mucositis (15%)

Hepatic: Hyperbilirubinemia (16%), increased serum ALT (11%)

Immunologic: Antibody development (children: 11%; IgE: 6%), development of IgG antibodies (18%; neutralizing 8%)

Infection: Sepsis (12%; serious: 5%)

Respiratory: Pharyngolaryngeal pain (14%)

Miscellaneous: Fever (46%)

1% to 10%:

Cardiovascular: Ischemic heart disease (≥2%), supraventricular arrhythmia (≥2%)

Endocrine & metabolic: Hyperphosphatemia (10%)

Gastrointestinal: Gastrointestinal infection (≥2%)

Hematologic & oncologic: Pulmonary hemorrhage (≥2%)

Hypersensitivity: Hypersensitivity (4%)

Infection: Infection (abdominal, ≥2%)

Respiratory: Respiratory failure (≥2%)

<1% (Limited to important or life-threatening): Anaphylaxis, hemolysis, methemoglobinemia, seizure

ALERT: U.S. Boxed Warning

Hypersensitivity reactions:

Rasburicase may cause serious and fatal hypersensitivity reactions, including anaphylaxis. Immediately and permanently discontinue rasburicase in patients who experience a serious hypersensitivity reaction.

Hemolysis:

Do not administer rasburicase to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Immediately and permanently discontinue rasburicase in patients developing hemolysis. Screen patients at higher risk for G6PD deficiency (eg, patients of African or Mediterranean ancestry) prior to starting rasburicase.

Methemoglobinemia:

Rasburicase can result in methemoglobinemia in some patients. Immediately and permanently discontinue rasburicase in patients developing methemoglobinemia.

Interference with uric acid measurements:

Rasburicase enzymatically degrades uric acid in blood samples left at room temperature. Collect blood samples in prechilled tubes containing heparin and immediately immerse and maintain sample in an ice water bath. Assay plasma samples within 4 hours of collection.

Warnings/Precautions

Concerns related to adverse effects:

• Hemolysis: [US Boxed Warning]: Due to the risk for hemolysis (<1%), rasburicase is contraindicated in patients with G6PD deficiency. Discontinue immediately and permanently in any patient developing hemolysis. Patients at higher risk for G6PD deficiency (eg, African or Mediterranean descent) should be screened prior to therapy. Severe hemolytic reactions occurred within 2 to 4 days of rasburicase initiation.

• Hypersensitivity: [US Boxed Warning]: Serious and fatal hypersensitivity reactions (including anaphylaxis) have been reported; immediately and permanently discontinue in patients developing a serious hypersensitivity reaction. Reactions may occur at any time during treatment (including the initial dose); signs and symptoms may include bronchospasm, chest pain/tightness, dyspnea, hypotension, hypoxia, shock, or urticaria. The safety and efficacy of more than one course of administration has not been established.

• Methemoglobinemia: [US Boxed Warning]: Methemoglobinemia has been reported (<1%). Discontinue immediately and permanently in any patient developing methemoglobinemia. Initiate appropriate treatment (eg, transfusion, methylene blue) if methemoglobinemia occurs.

Other warnings/precautions:

• Hydration: Patients at risk for tumor lysis syndrome should receive appropriate IV hydration as part of uric acid management; however, alkalinization (with sodium bicarbonate) concurrently with rasburicase is not recommended (Coiffier 2008).

• Multiple courses: Rasburicase is immunogenic and can elicit an antibody response; efficacy may be reduced with subsequent courses of therapy.

• Uric acid degradation: [US Boxed Warning]: Enzymatic degradation of uric acid in blood samples will occur if left at room temperature, which may interfere with serum uric acid measurements; specific guidelines for the collection of plasma uric acid samples must be followed, including collection in prechilled tubes with heparin anticoagulant, immediate ice water bath immersion and assay within 4 hours (sample should remain on ice until analyzed).

Monitoring Parameters

Plasma uric acid levels (4 hours after rasburicase administration, then every 6 to 8 hours until TLS resolution), CBC, G6PD deficiency screening (in patients at high risk for deficiency); monitor for hypersensitivity reactions

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. Use during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, anxiety, constipation, mouth irritation, or mouth sores. Have patient report immediately to prescriber signs of methemoglobinemia (blue or gray color of the lips, nails, or skin; abnormal heartbeat; seizures; severe dizziness or passing out; severe headache; fatigue; loss of strength and energy; or shortness of breath), jaundice, dark urine, pale skin, rash, fatigue, nausea, vomiting, diarrhea, abdominal pain, flu-like symptoms, pharyngitis, difficulty breathing, angina, shortness of breath, severe dizziness, passing out, severe loss of strength and energy, swelling of arms or legs, or coughing up blood (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.