英文药名: Lovenox HP(Enoxaparin Syringes)

中文药名: 依诺肝素注射剂

生产厂家: Aventis

药品名称

通用名称: 依诺肝素
常用名称: 依诺肝素钠
英文名称: Clexane, Enoxaparin Syringes
商品名称: Lovenox, 克赛
规格

20mg/0.2ml, 30mg/0.3ml, 40mg/0.4ml, 60mg/0.6ml, 80mg/0.8ml, 100mg/1ml, 120mg/0.8ml, 150mg/1ml
药理作用

本品为低分子量肝素制剂，有较强的抗凝血作用，还有溶血栓作用。
适应症　

适用于预防和治疗整形外科及外科手术后静脉血栓形成，防止血液透析时，体外循环过程凝血。
用法用量

①高血栓形成风险病人：术前12小时给予初始剂量40mg，术后每24小时皮下注射40mg。
低至中度血栓形成风险病人：术前2小时给予初始剂量20mg，术后每24小时皮下注射20mg。疗程为10-14日或至血栓形成风险消失。
②治疗已形成的静脉血栓：1mg/kg体重，q12h，皮下给药。
③体外循环(血液透析)：透析前给予单一剂量1mg/kg体重，以上剂量足够4小时的透析疗程(除非纤维蛋白环形成)，如需延长透析时间，每小时须追加上述剂量的1/4。
④不稳定型心绞痛和非Q波型心肌梗死：每12小时按1mg/kg体重皮下用药，持续2-8日，至临床症状稳定。
任何疑问,请遵医嘱!
注意事项

不宜与维生素K、抗血小板聚集药含阿司匹林、非甾体抗炎药、右旋糖酐等合用。本品不宜肌肉注射。
使用过量时，可用鱼精蛋白制剂作拮抗药解救。
每支药用后的余药保存不宜超过24小时。
慎用于肝脏功能不全、未控制的动脉性高血压、有胃肠道溃疡史的病人及孕妇。
哺乳期妇女使用应密切注意，避免乳房出血。
鉴于不同的低分子肝素并不等效，切不可在同一疗程中使用不同的产品。
本药不可与其他注射剂或静脉输注液混合。
背景介绍

*赛诺菲-安万特 (Sanofi-aventis) 宣布，美国食品与药物管理局 (FDA) 已经批准了抗凝血的 Lovenox(R)（依诺肝素钠注射液）的补充新药申请 (sNDA)。Lovenox(R) 用于治疗急性 ST 段抬高心肌梗死 (STEMI) 患者。Lovenox(R) 已经显示出可以减少周期性心肌梗塞综合终点的发生率，并可降低接受溶栓治疗、药物治疗或经皮冠状动脉介入治疗 (PCI) 的急性 STEMI 患者的死亡率。
*STEMI 是一种严重的心脏病，这种疾病表现为动脉通常完全被血栓所堵塞，累积足够长时间可导致心脏肌肉损坏。
*美国食品与药物管理局批准该补充新药申请书的依据是里程碑式的 ExTRACT-TIMI 25 试验（依诺肝素和溶栓灌注法用于治疗急性心肌梗塞，溶栓法治疗心肌梗塞-25研究）成果。参与 ExTRACT-TIMI 25 试验的有20,000多名急性 STEMI 患者。ExTRACT-TIMI 25 试验的结果已经公布在2006年4月6日刊发的《New England Journal of Medicine》（新英格兰医学杂志）上。
*ExTRACT-TIMI 25 研究表明，在接受了纤维蛋白溶解治疗的 STEMI 患者中，在三十天的时间里，依诺肝素较普通肝素 (UFH) 可极大地降低这些患者的死亡率和心肌梗塞的复发率，降幅为17%（9.9% 对 12.0%，p 值小于0.001）。与普通肝素相比较的时候依诺肝素显示出来的优点，均可在30内使用经皮冠状动脉介入治疗的随机选择的患者以及采用药物治疗的患者身上看到。采用依诺肝素进行治疗的组别里，30天的重大出血率（包括颅内出血率）为2.1%，而采用普通肝素的组别的重大出血率则为1.4% (p值小于0.001)。采用依诺肝素进行治疗的组别的死亡、非致命性心肌梗塞复发以及非致命性颅内出血（净临床优点的衡量尺度）的30天综合终点率明显低于采用普通肝素的组别（10.1% 对 12.2%，p值小于0.001）。
*ExTRACT-TIMI 25 研究的首席研究员、哈佛大学医学院 (Harvard Medical School) 医学教授、布莱根妇女医院 (Brigham and Women's Hospital) Samuel A. Levine 心脏科主管、TIMI Study Groups 高级研究员 Elliott Antman 医学博士表示：“在评估可治疗 STEMI 患者的治疗选择上，此次美国食品与药物管理局对该申请的批准是一个重要的里程碑。有了这一新指示，依诺肝素现在就可以应用到各种急性冠脉综合征的治疗当中。这些病症包括不稳定性心绞痛或非 ST 段抬高心肌梗死 (UA/NSTEMI) 以及 STEMI。”
*赛诺菲-安万特还在欧洲国家（包括法国、德国、英国、意大利和西班牙）已经提交了关于 STEMI 适应症的档案。
**冠状动脉疾病和急性冠脉综合征简介
*冠状动脉疾病 (CAD) 是全球最常见的一种心脏病，同时也是全世界最严重的健康问题。每年冠状动脉疾病夺去了大约1700万人的性命，也就是说全球每三个死亡的人当中就有一个死于冠状动脉疾病。美国心脏协会表示，超过1300万美国人都有过冠状动脉疾病病史，有750万人患有急性心脏病。
*急性冠脉综合征 (ACS) 是一个总称，用于形容因冠状动脉狭窄而导致的一组临床症状以及伴随有急性心肌局部缺血的任何类型的临床症状。急性心肌局部缺血是由冠状动脉疾病导致的心肌对氧的供求失衡所造成的。
*所有急性冠脉综合征都需要进行立即治疗。其治疗方法是多层面的，旨在尝试保护受损心肌免受进一步的损害、恢复动脉中的血液流动以及减轻心脏对氧的需求。在急诊室，首要目标是迅速鉴别 MI (STEMI) 患者，排除胸痛的其他原因，并把患者按照风险高低划分组别，提供适宜的治疗，以便把对心肌的损伤和心肌局部缺血降低到最小程度。
*血液回流到心脏（灌注法）可以通过使用某些药物（纤维蛋白溶解药）、摧毁血栓或通过手术（经皮冠状动脉介入治疗）进行治疗来实现。治疗急性冠脉综合征的药物选择包括：使用抗血小板药物来防止血小板粘合在一起从而形成血栓，使用抗凝血剂来阻止血栓。抗凝血剂可防止血栓进一步恶化以及新血栓的形成，但是抗凝血剂却不能够溶解血栓。
**Lovenox(R) 简介
*Lovenox(R) 是一种抗血栓形成药剂中的独特化学实体，是一种低分子肝素 (LMWH)。作为全球最畅销的低分子肝素，Lovenox(R) 可通过肝磷脂苄基酯的碱降解而得到，大约是普通肝素分子大小的三分之一。Lovenox(R) 是被人们研究最为广泛的低分子肝素，15年来治疗了96个国家的1.3亿名患者。
*Lovenox(R) 在美国获批用于与阿斯匹林一起预防不稳定心绞痛和非 Q 段（非 ST 抬高心肌梗死）的局部缺血并发症，用于治疗深静脉血栓 (DVT)。深静脉血栓可能导致肺动脉栓塞 (PE)，与苄丙酮香豆素钠 (warfarin sodium) 一起治疗急性深静脉血栓住院患者（无论有无肺动脉栓塞），以及与苄丙酮香豆素钠一起治疗无肺动脉栓塞的急性深静脉血栓门诊病人。其中的预防适用于可能会患得血栓并发症的作过腹部手术的患者、做过髋关节置换术的患者（正在住院治疗或住院治疗之后）以及患得急性病期间移动严重受限导致可能会患得血栓并发症的医疗患者。
**深静脉血栓和肺动脉栓塞简介
*深静脉血栓引起了身体深静脉内的血栓的形成，常常发生在较低的末端。每年，美国有多达两百万人患得深静脉血栓。肺动脉栓塞是深静脉血栓的一种严重并发症，有时可导致人丧命，每年美国有约300,000人死于这种并发症，多于乳腺癌和艾滋病致死人数的总和。
*深静脉血栓潜在的主要问题是阻碍了涉及到的深静脉内的血液流动，这是由于在深静脉内形成了血栓。血液流动不畅可导致急性的腿疼和肿胀等症状。血栓的部分从深静脉的形成位置被驱逐出来，随着血液流动而在血管中行走，最后抵达肺部并留在那里的时候便形成了肺动脉栓塞。有很多与肺动脉栓塞有关的症状，但是最常见的包括呼吸急促以及在深呼吸时侧胸疼痛加剧。有很多可导致深静脉血栓的常见的风险因素，其中包括长期不能移动、大型手术、慢性病、癌症、年龄大于40岁、外伤、口服避孕药、怀孕以及产后。
*深静脉血栓的治疗办法包括在某些危险疾病情况下进行预防以及对确诊的深静脉血栓患者进行急性治疗。对深静脉血栓的治疗有几种治疗办法，其中包括提早活动、抗血栓压力带或器械、腿部压力设备以加强血液流动，还有抗凝血剂和/或血液稀释药物。就与深静脉血栓有关的迹象和症状向您的医疗保健专业人士进行咨询是非常重要的。
**赛诺菲-安万特简介
*赛诺菲-安万特集团是制药行业中的全球领先企业之一，在欧洲排名第一。依靠着世界级的研发机构，赛诺菲-安万特在七大治疗领域占据了领导地位：心血管、血栓形成、肿瘤、代谢病、中枢神经系统、内科和疫苗。赛诺菲-安万特集团在巴黎 (EURONEXT: SAN) 和纽约 (NYSE: SNY) 上市交易。

包装规格：

·100mg/1ml 10(支)
·20mg/0.2ml 4(支)
·30mg/0.3ml 10(支) 
·40mg/0.4ml 2(支) 
·60mg/0.6ml 2(支) 
·80mg/0.8ml 2(支)  

Enoxaparin SodiumPronunciation: (ee-nox-AP-a-rin SO-dee-um)Class: Low molecular weight heparin (LMWH)
Trade Names:Lovenox- Injection 30 mg per 0.3 mL- Injection 40 mg per 0.4 mL- Injection 60 mg per 0.6 mL- Injection 80 mg per 0.8 mL- Injection 100 mg/mL- Injection 120 mg per 0.8 mL- Injection 150 mg/mL- Injection 300 mg per 3 mL

Lovenox HP
Pharmacology
Causes higher anti-factor Xa to antithrombin activities (anti-factor IIa) ratio than heparin, which may prevent thrombosis.

Pharmacokinetics
Absorption
Bioavailability is 92%.

Distribution
Vd is approximately 6 L (for anti-factor Xa activity).

Metabolism
Metabolized in the liver by desulfation and/or depolymerization to low molecular weight species.

Elimination
Cl is approximately 15 mL/min. The t ½ is 4.5 h (based on anti-factor Xa activity).

Peak
3 to 5 h.

Special Populations
Renal Function Impairment
Cl is approximately 30% lower in those with severe renal function impairment (CrCl less than 30 mL/min).

Gender
Apparent clearance and maximum observed activity derived from anti-Factor Xa values following subcutaneous dosing were slightly higher in males than in females.

Weight
Mean AUC of anti-Factor Xa activity is marginally higher at steady state in obese healthy patients.

Indications and Usage
Prevention of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing hip or knee replacement surgery or abdominal surgery; in conjunction with warfarin for inpatient treatment of acute DVT with or without PE, or outpatient treatment of acute DVT without PE; prevention of ischemic complications of unstable and non–Q-wave MI when coadministered with aspirin. In medical patients who are at risk for thromboembolic complications because of severely restricted mobility during acute illness.

Treatment of acute ST-segment elevation MI (STEMI).

Contraindications
Hypersensitivity to enoxaparin, heparin, benzyl alcohol, or pork products; active major bleeding; thrombocytopenia associated with positive in vitro test for antiplatelet antibody in presence of enoxaparin.

Dosage and Administration
Hip or Knee Replacement SurgeryAdults
Subcutaneous 30 mg twice daily, with initial dose given within 12 to 24 h postoperatively, provided hemostasis has been established. Average duration of administration is 7 to 10 days, up to 14 days. For hip replacement surgery, 40 mg every day, given initially 9 to 15 h prior to surgery may be considered; continue prophylaxis for 3 wk.

Abdominal SurgeryAdults
Subcutaneous 40 mg/day with the initial dose given 2 h prior to surgery. Usual duration of administration is 7 to 10 days, up to 12 days.

Acute IllnessAdults
Subcutaneous 40 mg every day for 6 to 11 days, up to 14 days, in patients at risk for thromboembolic complications caused by severely restricted mobility during acute illness.

DVT/PE TreatmentAdults, Outpatient
Subcutaneous 1 mg/kg every 12 h.

Adults, Inpatient
Subcutaneous 1 mg/kg every 12 h or 1.5 mg/kg every day (same time each day).

Adults, Outpatient and Inpatient
Initiate warfarin therapy when appropriate (usually within 72 h of enoxaparin). Continue enoxaparin for a minimum of 5 days and until a therapeutic anticoagulant effect has been achieved. The average duration is 7 days; up to 17 days has been well tolerated.

Unstable Angina/Non–Q-Wave MIAdults
Subcutaneous 1 mg/kg every 12 h in conjunction with oral aspirin therapy (100 to 325 mg every day); usual duration of treatment is 2 to 8 days, up to 12.5 days.

Acute STEMIAdults
IV/Subcutaneous Single IV bolus of 30 mg plus a 1 mg/kg subcutaneous dose followed by 1 mg/kg every 12 hr (max, 100 mg for first 2 doses only, followed by 1 mg/kg dosing for the remaining doses).

Renal Function ImpairmentAdults
Subcutaneous No dosage adjustment is recommended for mild (CrCl 50 to 80 mL/min) or moderate (CrCl 30 to 50 mL/min) impairment. Severe renal function impairment (Crcl less than 30 mL/min):

Prophylaxis in abdominal surgery or hip or knee replacement surgery; prophylaxis in medical patients during acute illness
30 mg subcutaneous once daily.

Inpatient DVT with or without PE in conjunction with warfarin; outpatient treatment of DVT without PE in conjunction with warfarin; prophylaxis of ischemic complications of unstable angina and non–Q-wave MI in conjunction with aspirin; acute STEMI in patients 75 yr of age or older (no initial bolus)
1 mg/kg subcutaneous once daily.

Acute STEMI in patients younger than 75 yr of age
30 mg IV bolus plus 1 mg/kg subcutaneously followed by 1 mg/kg subcutaneously once daily.

ElderlyAdults
For treatment of acute STEMI in elderly patients at least 75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg subcutaneous every 12 h (max 75 mg for the first 2 doses only, followed by 0.75 mg/kg dosing for the remaining doses).

General Advice
Enoxaparin is a clear, colorless to pale yellow solution and should be inspected visually for particulate matter and discoloration prior to administration.
Do not administer by IM injection.
With patient lying down, administer drug by subcutaneous injection. Alternate administration between left and right anterolateral and posterolateral abdominal wall. Introduce whole length of needle into skinfold held between thumb and forefinger; hold skinfold throughout injection.
Do not aspirate into syringe; do not rub site after injection. These activities may cause tissue damage and subcutaneous bleeding.
Storage/Stability
Store at room temperature (59° to 86°F). Do not freeze.

Drug Interactions
Anticoagulants, NSAIDs, platelet inhibitors
Use enoxaparin with caution because of increased risk of hemorrhagic reactions.

Incompatibility
Do not mix enoxaparin with other injections or infusions.

Laboratory Test Interactions
Transaminase determinations
Drug causes asymptomatic elevations in AST and ALT.

Adverse Reactions
CNS
Confusion (2%).

Dermatologic
Cutaneous vasculitis, purpura, vesiculobullous rash (postmarketing).

GI
Nausea (3%); diarrhea (2%).

Genitourinary
Hematuria (2%).

Hematologic-Lymphatic
Anemia (16%); hemorrhage (13%); major bleeding (4%); thrombocytopenia (3%); thrombocytopenia with thrombosis, thrombocytosis (postmarketing).

Lab Tests
Increased AST and ALT greater than 3 times ULN (6%); hyperlipidemia, hypertriglyceridemia (postmarketing).

Local
Injection-site hemorrhage (5%); ecchymosis (3%); injection-site pain (2%); erythema, hematoma, mild local irritation, pain, injection-site reactions, including anaphylactoid reactions, pruritus, urticaria (postmarketing).

Miscellaneous
Fever (8%); peripheral edema (6%); dyspnea epidural (3%); spinal hematoma (postmarketing).

Precautions

Warnings Spinal/Epidural hematomas Risk of spinal/epidural hematoma increased in patients receiving neuraxial anesthesia or spinal puncture and who are anticoagulated with LMWH or heparinoids. Other risk factors include indwelling epidural catheters, repeated or traumatic epidural or spinal puncture, or other drugs affecting hemostasis (eg, NSAIDs, platelet inhibitors, anticoagulants). Risk of long-term or permanent paralysis. Monitor frequently for signs/symptoms of neurological impairment.

Monitor Periodic CBCs, including platelet count, and stool occult blood tests are recommended

Pregnancy
Category B .

Lactation
Undetermined.

Children
Safety and efficacy not established.

Elderly
Delayed elimination of drug possible. Use with caution.

Renal Function
Delayed elimination of drug may occur. Use with caution.

Hepatic Function
Dosage adjustments are recommended in severe hepatic function impairment.

Special Risk Patients
Use drug with caution in patients with diabetic retinopathy, bleeding diathesis, uncontrolled arterial hypertension, or history of recent GI ulceration and hemorrhage.

Benzyl alcohol
Multiple-dose vials contain benzyl alcohol as a preservative; has been associated with a fatal “gasping syndrome” in premature neonates.

Hemorrhage
Use drug with extreme caution in patients with conditions associated with increased risk of hemorrhage.

Interchangeability with heparin
Cannot be used interchangeably (unit for unit) with heparin or other LMWHs.

Percutaneous coronary revascularization procedures
To minimize the risk of bleeding, adhere precisely to the recommended dosing intervals.

Prosthetic heart valves
Use is not recommended for thromboprophylaxis in patients with prosthetic heart valves.

Teratogenesis
There have been reports of congenital anomalies in infants born to women who received enoxaparin during pregnancy, including cerebral anomalies, limb anomalies, hypospadias, peripheral vascular malformation, fibrotic dysplasia, and cardiac defects. A cause-and-effect relationship has not been established.

Thrombocytopenia
Use with extreme caution in patients who have a history of heparin-induced thrombocytopenia. Closely monitor any degree of thrombocytopenia.

Overdosage
Symptoms
Hemorrhage.

Patient Information
Instruct patient to report any signs of bleeding or bruising, or black, bloody, or tarry stools immediately.
If patient has home therapy, teach patient or family member proper subcutaneous injection technique.
Caution patient to take safety precautions to prevent cuts and bruising (eg, use electric razor, soft toothbrush, handrails).