英文药名: Fragmin(Dalteparin Solution for Injection) 中文药名: 法安明（达肝素注射液） 生产厂家: Pfizer 药品名称 英文药名: Fragmin (Dalteparin Injection) 中文药名: 法安明（达肝素注射液) 生产厂家 Pfizer 辉瑞 性状 本药是一种抗血栓形成剂，含有达肝素钠（低分子量肝素钠）以及非活性成分如氯化钠或注射用水。 药理作用 达肝素钠是从猪肠粘膜制备的肝素钠通过可控亚硝酸解聚作用而生产的。其平均相对分子质量为5000。达肝素钠的抗血栓形成作用通过抗凝血酶而加强抑制凝血因子Xa和凝血酶。达肝素钠加强抑制凝血因子Xa的能力，相对大于延长凝血时间的能力。达肝素钠对血小板功能和血小板粘附性的影响比肝素小，因而对初级阶段止血只有很小的作用。尽管如此，达肝素钠的某些抗血栓形成的特性被认为是通过对血管壁或纤维蛋白溶解系统的作用而形成的。 药代动力学 静脉注射后的半衰期为2小时，皮下注射后为3-4小时。皮下注射后的生物利用率约为90% ；药物动力学基本上是非剂量依赖性的。 适应症 急性深静脉血栓的治疗。急性肾功能衰竭或慢性肾功能不全者进行血液透析和血液过滤期间防止体外循环系统中发生凝血。不稳定型冠心病，如不稳定型心绞痛和非Q-波型心肌梗塞。预防与手术有关的血栓形成。 用法用量 急性深静脉血栓的治疗 既可以皮下注射每日1次，也可每日2次。 *每日一次用法：200iu/kg体重，每日1次皮下注射，不需要监测抗凝血作用，每日总量不超过18000iu。 *每日二次用法：100iu/kg体重，皮下注射每日2次，该剂量适用于出血危险较高的患者。 通常治疗中无需要监测、但可进行功能性抗-Xa测定。皮下注射后3-4小时取血样，可测得最高血浆浓度。推荐的血浆浓度范围为0.5-1 iu抗-Xa/mL。用本药的同时可立即口服维生素K拮抗剂。本药的治疗应持续到凝血酶原复合物水平（因子II、VII、IX、X）降至治疗水平。通常联合治疗至少需要5天。 血液透析和血液过滤期间预防凝血 慢性肾功能衰竭，患者无已知的出血危险： *血液透析和血液过滤不超过4小时：剂量如下或静脉快速注射5000 iu。 *血液透析和血液过滤超过4小时：静脉快速注射30-40 iu/kg体重，继以静脉输注10-15 iu/kg体重/hr。 正常情况下，患者进行长期血液透析应用本药时，需要调整剂量的次数很少，因而检测抗-Xa浓度的次数也很少。给予的剂量通常使血浆浓度保持在0.5-1 iu抗-Xa/mL的范围内。 急性肾功能衰竭，患者有高度出血危险：静脉快速注射5-10 iu/kg体重，继以静脉输注4-5 iu/kg体重/hr。进行急性血液透析的患者治疗间歇较短，应对抗-Xa浓度进行全面监测。血浆浓度应保持在0.2-0.4 iu抗-Xa/mL的范围内。 不稳定型冠心病 皮下注射120iu/kg体重，每日2次，最大剂量为10000iu/12小时。至少治疗6天，可根据病情酌情延长用药时间，推荐同时使用低剂量乙酰水杨酸。 预防与手术有关的血栓形成 伴有血栓栓塞并发症危险的大手术：术前1-2小时皮下注射2500iu，术后每天早晨皮下注射2500iu，直至患者可活动，一般需5-7天或更长。 具有其它危险因素的大手术和矫形手术：术前晚间皮下注射5000iu，术后每晚皮下注射5000iu，治疗须持续到患者可活动为止，一般需5-7天或更长。另外，也可术前1-2小时皮下注射2500iu，术后8-12小时皮下注射2500iu，然后每日早皮下注射5000 iu。 任何疑问，请遵医嘱！ 不良反应 特别在大剂量时，可能引起出血，常见报道的副作用是注射部位皮下血静肿。罕见血小板减少症、皮肤坏死、过敏反应和出血。曾观察到肝转氨酶（AST、ALT）一过性轻度至中等度升高。少见于过敏样反应。 禁忌症 对本药过敏。急性胃十二指肠溃疡和脑出血。严重凝血疾患。脓毒性心内膜炎。中枢神经系统、眼及耳受伤或手术。用达肝素钠时体外血小板聚集试验结果阳性的血小板减少症病人。治疗急性深静脉血栓形成时伴用局部麻醉。 警告 各种低分子质量肝素的特性不同，推荐的剂量也不同，因此需要特别小心，并必须遵守各种特定产品的使用方法。不可经肌肉内途径给药。 注意事项 对于血小板减少症和血小板缺陷、严重肝及肾功能不全、未控制的高血压、高血压性或糖尿病性视网膜病以及已知对肝素及/或低分子质量肝素过敏者，建议慎用此药。对新近手术的病人应用大剂量本药治疗时，也应小心。达肝素钠对于凝血时间，例如APTT（部分凝血酶原时间）或凝血酶时间。只有轻微的延长作用。建议用抗Xa方法作为实验室监测。延长APTT而增加剂量，可能引起用药过量和出血。应用本药进行慢性血液透析的病人通常只需要少数几次剂量调整，所以只需要少数几次检查抗Xa浓度即可。进行急性血液透析的病人的治疗间歇较短，应接受抗Xa浓度的全面监测。 孕妇及哺乳期妇女用药 曾在孕妇中测定过本药，没有见到对妊娠过程以及对胎儿和新生儿健康的有害影响。但在妊娠期间不应该使用含防腐剂的注射液，因为它含有苯甲醇，后者可能通过胎盘。必须记住，如在分娩或剖腹产前给予苯甲醇，这对早产儿有潜在的毒性。尚无资料证明达肝素钠是否进入母乳。 药物相互作用 同时应用对止血有影响的药物，例如乙酰水杨酸、非类固醇抗炎药、维生素K拮抗剂及葡聚糖，可能加强本药的抗凝作用。 药物过量 鱼精蛋白可抑制达肝素钠引起的抗凝作用。所引起的凝血时间的延长可被完全抵消，但抗Xa活性只抵消约25-50%，每1 mg鱼精蛋白可抑制100 IU抗Xa的达肝素钠的作用。鱼精蛋白本身对初级阶段止血有抑制作用，所以只能在紧急情况下应用。 用药须知 本药可加于玻璃输液瓶或塑料容器装的等渗氯化钠或等渗葡萄糖输注液，该溶液应在12小时内使用。本药和其它产品的相容性尚未调查。 贮藏 可在最高30°C的室温下存放。小瓶装的含防腐剂的法安明溶液应在第一次打开小瓶后14天内使用，过期不可再用。 Fragmin Graduated Syringe 10,000 IU/ml Solution for Injection 1. Name of the medicinal product Fragmin® Graduated Syringe 10,000 IU/ml Solution for Injection 2. Qualitative and quantitative composition Pre-filled, single dose syringes containing dalteparin sodium 10,000 IU (anti-Factor Xa) in 1.0 ml solution for injection. Fragmin Graduated Syringes do not contain preservatives. *Potency is described in International anti-Factor Xa units (IU) of the 1st International Standard for Low Molecular Weight Heparin. 3. Pharmaceutical form Solution for injection. 4. Clinical particulars 4.1 Therapeutic indications Unstable angina and non-Q wave myocardial infarction (unstable coronary artery disease-UCAD), administered concurrently with aspirin. Extended Use Fragmin may be used beyond 8 days in patients awaiting angiography/revascularisation procedures (see Section 5.1) 4.2 Posology and method of administration Adults 120 IU/kg body weight are administered subcutaneously 12 hourly for up to 8 days if considered of benefit by the physician. Maximum dose is 10,000 IU/12 hours. Patients needing treatment beyond 8 days, while awaiting angiography/revascularisation, should receive a fixed dose of either 5,000 IU (women < 80 kg and men <70 kg) or 7,500 IU (women ≥80 kg and men ≥70 kg) 12 hourly. Treatment is recommended to be given until the day of the revascularisation procedure (PTCA or CABG) but not for more than 45 days. Paediatric population The safety and efficacy of dalteparin sodium in children has not been established. Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made. Monitoring Anti-Xa levels in children Measurement of peak anti-Xa levels at about 4 hours post-dose should be considered for certain special populations receiving Fragmin, such as children. For therapeutic treatment with doses administered once daily, peak anti-Xa levels should generally be maintained between 0.5 and 1.0 IU/mL measured at 4 hours post-dose. In the case of low and changing physiologic renal function such as in neonates, close monitoring of anti-Xa levels is warranted. For prophylaxis treatment the anti- Xa levels should generally be maintained between 0.2-0.4 IU/mL. As with all antithrombotic agents, there is a risk of systemic bleeding with Fragmin administration. Care should be taken with Fragmin use in high dose treatment of newly operated patients. After treatment is initiated patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain and periodic measurements of hemoglobin, and anti-Xa determinations. Elderly Fragmin has been used safely in elderly patients without the need for dosage adjustment. Method of administration Following the determination of the required dose, excess solution should be ejected from the syringe. Administration is by subcutaneous injection, preferably into the abdominal subcutaneous tissue anterolaterally or posterolaterally, or into the lateral part of the thigh. Patients should be supine and the total length of the needle should be introduced vertically, not at an angle, into the thick part of a skin fold, produced by squeezing the skin between thumb and forefinger; the skin fold should be held throughout the injection. Syringes should be discarded after use 4.3 Contraindications Known hypersensitivity to Fragmin or other low molecular weight heparins and/or heparins e.g. history of confirmed or suspected immunologically mediated heparin induced thrombocytopenia (type II); acute gastroduodenal ulcer; cerebral haemorrhage; known haemorrhagic diathesis or other active haemorrhage; serious coagulation disorders; acute or sub-acute septic endocarditis; injuries to and operations on the central nervous system, eyes and ears. In patients receiving Fragmin for treatment rather than prophylaxis, local and/or regional anaesthesia in elective surgical procedures is contra-indicated with high doses of dalteparin (such as those needed to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery disease). 4.4 Special warnings and precautions for use Do not administer by the intramuscular route. Due to the risk of haematoma, intramuscular injection of other medical preparations should be avoided when the twenty-four hour dose of dalteparin exceeds 5,000 IU. Caution should be exercised in patients in whom there is an increased risk of bleeding complications, e.g. following surgery or trauma, haemorrhagic stroke, severe liver or renal failure, thrombocytopenia or defective platelet function, uncontrolled hypertension, hypertensive or diabetic retinopathy, patients receiving concurrent anticoagulant/antiplatelet agents (see Interactions Section). Caution shall also be observed at high-dose treatment with dalteparin (such as those needed to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery disease). It is recommended that platelets be counted before starting treatment with Fragmin and monitored regularly. Special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100,000/µl) associated with positive or unknown results of in-vitro tests for anti-platelet antibody in the presence of Fragmin or other low molecular weight (mass) heparins and/or heparin. Fragmin induces only a moderate prolongation of the APTT and thrombin time. Accordingly, dosage increments based upon prolongation of the APTT may cause overdosage and bleeding. Therefore, prolongation of the APTT should only be used as a test of overdosage. Monitoring Anti-Xa Levels Monitoring of Anti-Xa Levels in patients using Fragmin is not usually required but should be considered for specific patient populations such as paediatrics, those with renal failure, those who are very thin or morbidly obese, pregnant or at increased risk for bleeding or rethrombosis Where monitoring is necessary, laboratory assays using a chromogenic substrate are considered the method of choice for measuring anti-Xa levels. Activated partial thromboplastin time (APTT) or thrombin time should not be used because these tests are relatively insensitive to the activity of dalteparin. Increasing the dose of dalteparin in an attempt to prolong APTT may result in bleeding (see section 4.9). Patients under chronic haemodialysis with dalteparin need as a rule fewer dosage adjustments and as a result fewer controls of anti-Xa levels. Patients undergoing acute haemodialysis may be more unstable and should have a more comprehensive monitoring of anti-Xa levels (see section 5.2). Patients with severely disturbed hepatic function may need a reduction in dosage and should be monitored accordingly. If a transmural myocardial infarction occurs in patients where thrombolytic treatment might be appropriate, this does not necessitate discontinuation of treatment with Fragmin but might increase the risk of bleeding. As individual low molecular weight (mass) heparins have differing characteristics, switching to an alternative low molecular weight heparin should be avoided. The directions for use relating to each specific product must be observed as different dosages may be required. Interchangeability with other anticoagulants Dalteparin cannot be used interchangeably (unit for unit) with unfractionated heparin, other low molecular weight heparins, or synthetic polysaccharides. Each of these medicines differ in their starting raw materials, manufacturing process, physico-chemical, biological, and clinical properties, leading to differences in biochemical identity, dosing, and possibly clinical efficacy and safety. Each of these medicines is unique and has its own instructions for use. Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium sparing drugs. The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days. When neuraxial anaesthesia (epidural/spinal anaesthesia) or spinal puncture is employed, patients are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters or by the concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. Patients should be monitored frequently for signs and symptoms of neurological impairment when anticoagulation is given in connection with epidural/spinal anesthesia. Insertion or removal of the epidural or spinal catheter should be postponed to 10-12 hours after dalteparin doses administered for thrombosis prophylaxis, while in those receiving higher therapeutic dalteparin doses (such as 100 IU/kg -120 IU/kg every 12 hours or 200 IU/kg once daily), the interval should be a minimum of 24 hours. Should a physician, as a clinical judgement, decide to administer anticoagulation in the context of epidural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment such as back pain, sensory or motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction. Nurses should be trained to detect such signs and symptoms. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these. If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment may include spinal cord decompression. There have been no adequate studies to assess the safe and effective use of Fragmin in preventing valve thrombosis in patients with prosthetic heart valves. Prophylactic doses of Fragmin are not sufficient to prevent valve thrombosis in patients with prosthetic heart valves. The use of Fragmin cannot be recommended for this purpose. At long-term treatment of unstable coronary artery disease, such as e.g., before revascularisation, dose reduction should be considered at reduced kidney function (S-creatinine > 150 μmol/l). Paediatric population: Clinical experience of treatment of children is limited. If dalteparin is used in children the anti-Xa levels should be monitored. The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal “Gasping Syndrome” (see section 4.6). Elderly patients (especially patients aged eighty years and above) may be at an increased risk for bleeding complications within the therapeutic dosage ranges. Careful clinical monitoring is advised. 4.5 Interaction with other medicinal products and other forms of interaction The possibility of the following interactions with Fragmin should be considered: i) An enhancement of the anticoagulant effect by anticoagulant/antiplatelet agents e.g. aspirin/dipyridamole, GP IIb/IIIa receptor antagonists, vitamin K antagonists, NSAIDs e.g. indomethacin, cytostatics, dextran, thrombolytics, sulphinpyrazone, probenecid, and ethacrynic acid. However, unless specifically contra-indicated, patients should receive oral low-dose aspirin. ii) A reduction of the anticoagulant effect may occur with concomitant administration of antihistamines, cardiac glycosides, tetracycline and ascorbic acid. Because NSAIDs and ASA analgesic/anti-inflammatory doses reduce production of vasodilatatory prostaglandins, and thereby renal blood flow and the renal excretion, particular care should be taken when administering dalteparin concomitantly with NSAIDs or high dose ASA in patients with renal failure. However, if there are no specific contraindications, patients with unstable coronary artery disease (unstable angina and non-Q-wave infarction) can be treated with low doses of acetylsalicylic acid. As heparin has been shown to interact with intravenous nitroglycerine, high dose penicillin, quinine and tobacco smoking interaction cannot be ruled out for dalteparin. Paediatric population Interaction studies have only been studied in adults. 4.6. Fertility, pregnancy and lactation Pregnancy Dalteparin does not pass the placenta. A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity. Fragmin can be used during pregnancy if clinically needed. If dalteparin is used during pregnancy, the possibility of foetal harm appears remote. However, because the possibility of harm cannot be completely ruled out, dalteparin should be used during pregnancy only if clearly needed. There are more than 2,000 published cases (studies, case series and case reports) on administration of dalteparin in pregnancy. As compared with unfractionated heparin, a lower bleeding tendency and reduced risk of osteoporotic fracture was reported. The largest prospective study “Efficacy of Thromboprophylaxis as an Intervention during Gravidity“ (EThIG), involved 810 pregnant women and investigated a pregnancy-specific scheme for risk stratification (low, high, very high risk of venous thromboembolism) with daily doses of dalteparin between 50 – 150 IU/kg body weight (in single cases up to max. 200 IU/kg body weight). However, only limited randomised controlled studies are available on the use of low molecular weight heparins in pregnancy. Animal experiments did not show any teratogenic or fetotoxic properties of dalteparin (see section 5.3). Epidural anaesthesia during childbirth is absolutely contraindicated in women who are being treated with high-dose anticoagulants (see section 4.3). Caution is recommended when treating patients with an increased risk of haemorrhage, such as perinatal women (see section 4.4). In pregnant women during the last trimester, dalteparin anti-Xa half-lives of 4 to 5 hours were measured. Fragmin 25000 100,000 IU/4ml multidose vial contains benzyl alcohol as a preservative. As benzyl alcohol may cross the placenta, Fragmin without preservative should therefore be used during pregnancy (see section 4.4). Therapeutic failures have been reported in pregnant women with prosthetic heart valves on full anti-coagulant doses of low molecular weight heparin. In the absence of clear dosing, efficacy and safety information in this circumstance, Fragmin is not recommended for use in pregnant women with prosthetic heart valves. Breast-feeding Limited data are available for excretion of dalteparin in human milk. One study in 15 women (between day 3 and 5 of lactation and 2 to 3 hours after receiving prophylactic doses of dalteparin) detected small amounts of anti- factor Xa levels of 2 to 8% of plasma levels in breast milk, equivalent to a milk/plasma ratio of <0.025-0.224. An anticoagulant effect on the infant appears unlikely. A risk to the suckling child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Fragmin should be made taking into account the benefit of breast-feeding to the child and the benefit of Fragmin therapy to the woman. Fertility Based on current clinical data there is no evidence that dalteparin sodium effects fertility. No effects on fertility, copulation or peri- and postnatal development were noted when dalteparin sodium was tested in animals. 4.7 Effects on ability to drive and use machines Fragmin does not affect the ability to drive or operate machinery. 4.8 Undesirable effects About 3% of the patients having had prophylactic treatment reported side-effects. The reported adverse reactions, which may possibly be associated to dalteparin sodium, are listed in the following table by system organ class and frequency group: common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10 000). System Organ Class Frequency Adverse reactions Blood and lymphatic system disorders Common Mild thrombocytopenia (type I), which usually is reversible during the treatment Not Known* Immunologically-mediated heparin-induced thrombocytopenia (type II, with or without associated thrombotic complications) Immune system disorders Uncommon Hypersensitivity Not Known* Anaphylactic reactions Nervous System Disorders Not Known* Intracranial bleeds have been reported and some have been fatal Cardiac disorders Not Known* Prosthetic cardiac valve thrombosis Vascular disorders Common Haemorrhage Gastrointestinal disorders Not Known* Retroperitoneal bleeds have been reported and some have been fatal Hepatic and biliary disorders Common Transient elevation of transaminases Skin and subcutaneous tissue disorders Uncommon Urticaria, pruritus Rare Skin necrosis, transient alopecia Not Known* Rash General disorders and administration site conditions Common Subcutaneous haematoma at the injection site Pain at the injection site Injury, poisoning and procedural complications Not Known* Spinal or epidural hematoma *(cannot be established from available data) The risk of bleeding is depending on dose. Most bleedings are mild. Severe bleedings have been reported, some cases with fatal outcome. Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalaemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see section 4.4). Long term treatment with heparin has been associated with a risk of osteoporosis. Although this has not been observed with dalteparin, the risk of osteoporosis cannot be excluded. Paediatric population Frequency, type and severity of adverse reactions in children are expected to be the same as in adults. The safety of long term dalteparin administration has not been established. 4.9 Overdose The anticoagulant effect (i.e. prolongation of the APTT) induced by Fragmin is inhibited by protamine. Since protamine itself has an inhibiting effect on primary haemostasis it should be used only in an emergency. The prolongation of the clotting time induced by Fragmin may be fully neutralised by protamine, but the anti-Factor Xa activity is only neutralised to about 25-50%. 1 mg of protamine inhibits the effect of 100 IU (anti-Factor Xa) of Fragmin. Protamine should be given by intravenous injection over approximately 10 minutes. 5. Pharmacological properties 5.1 Pharmacodynamic properties ATC code BOIA B Dalteparin sodium is a low molecular weight heparin fraction (average molecular weight 4000-6000 Daltons) produced from porcine-derived sodium heparin. Mechanism of action Dalteparin sodium is an antithrombotic agent, which acts mainly through its ability to potentiate the inhibition of Factor Xa and thrombin by antithrombin. It has a relatively higher ability to potentiate Factor Xa inhibition than to prolong plasma clotting time (APTT). Pharmacodynamic effects Compared with standard, unfractionated heparin, dalteparin sodium has a reduced adverse effect on platelet function and platelet adhesion, and thus has only a minimal effect on primary haemostasis. Some of the antithrombotic properties of dalteparin sodium are thought to be mediated through the effects on vessel walls or the fibrinolytic system. Clinical efficacy and safety In a prospectively randomised study in 3489 patients (FRISC II) with acute coronary syndromes, early invasive strategy was clearly superior to non –invasive strategy. In a post-hoc analysis, the extended use of Fragmin, up to Day 45 reduced the incidence of death and/or MI compared with placebo in the non-invasive group (revascularisation only if necessary). The use of Fragmin beyond 8 days did not significantly reduce the incidence of death and/or MI, compared to placebo, in patients who were contraindicated to early angiography and revascularisation. Paediatric population There is limited safety and efficacy information on the use of dalteparin in paediatric patients. If dalteparin is used in these patients, anti-Xa levels should be monitored. The largest prospective study investigated the efficacy, safety and relation of dose to plasma anti-Xa activity of dalteparin in prophylaxis and therapy of arterial and venous thrombosis in 48 paediatric patients (Nohe et al, 1999). Nohe et al (1999) Study Demographics and Trial Design Trial design Patients Diagnosis Indication, Fragmin Dose, Target anti-Xa, Duration Single-center, open label trial; (n = 48) Age: 31 week preterm to 18 years Gender: 32 males, 16 females Arterial or venous thrombosis; PVOD; PPH Prophylaxis: (n = 10) 95 ± 52 anti-Xa IU/kg sc qd; 0.2 to 0.4 IU/mL 3-6 months Primary Therapy: (n = 25) 129 ± 43 anti-Xa IU/kg sc qd; 0.4 to 1.0 IU/mL 3-6 months Secondary Therapy: (n = 13) 129 ± 43 anti-Xa IU/kg sc qd; 0.4 to 1.0 IU/mL 3-6 months In this study, no thromboembolic events occurred in the 10 patients receiving dalteparin for thromboprophylaxis. In the 23 patients given dalteparin for primary antithrombotic therapy of arterial or venous thrombosis, complete recanalization was seen in 7/23 (30%), partial recanalization in 7/23 (30%) and no recanalization in 9/23 (40%). In the 8 patients administered dalteparin for secondary antithrombotic therapy following successful thrombolysis, recanalisation was maintained or improved. In the 5 patients receiving dalteparin for secondary therapy following failed thrombolysis, no recanalization was seen. Minor bleeding, reported in 2/48 children (4%), resolved after dose reduction. Patient platelet counts ranged from 37,000/μl to 574,000/μl. The authors attributed platelet counts below normal (150,000/μl) to immunosuppressive therapy. A reduction in platelet count ≥ 50% of the initial value, a sign of heparin-induced thrombocytopenia type 2 (HIT 2), was not observed in any patient. For both prophylaxis and therapy groups, the dalteparin doses (anti-Xa IU/kg) required to achieve target anti-Xa activities (IU/ml) were inversely related to age (r2 = 0.64, P = 0.017; r2 = 0.13, P = 0.013). The predictability of the anticoagulant effect with weight-adjusted doses appears to be reduced in children compared to adults, presumably due to altered plasma binding (see section 5.2). 5.2 Pharmacokinetic properties Elimination The half-life following s.c. administration is 3.5-4 hours, twice that of unfractionated heparin. Bioavailability The bioavailability following s.c. injection is approximately 87 per cent and the pharmacokinetics are not dose dependent. The half life is prolonged in uraemic patients as dalteparin sodium is eliminated primarily through the kidneys. Special Populations Haemodialysis: In patients with chronic renal insufficiency requiring haemodialysis, the mean terminal hal-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU dalteparin was 5.7 ± 2.0 hours, i.e. considerably longer than values observed in healthy volunteers, therefore, greater accumulation can be expected in these patients. Paediatric Population: Infants less than approximately 2 to 3 months of age or < 5 kg have increased LMWH requirements per kg likely due to their larger volume of distribution. Alternative explanations for the increased requirement of LMWH per body weight in young children include altered heparin pharmacokinetics and/or a decreased expression of anticoagulant activity of heparin in children due to decreased plasma concentrations of antithrombin. 5.3 Preclinical safety data The acute toxicity of dalteparin sodium is considerably lower than that of heparin. The only significant finding, which occurred consistently throughout the toxicity studies after subcutaneous administration of the higher dose levels was local haemorrhage at the injection sites, dose-related in incidence and severity. There was no cumulative effect on injection site haemorrhages. The haemorrhagic reaction was reflected in dose related changes in the anticoagulant effects as measured by APTT and anti-Factor Xa activities. It was concluded that dalteparin sodium did not have a greater osteopenic effect than heparin since at equivalent doses the osteopenic effect was comparable. The results revealed no organ toxicity irrespective of the route of administration, doses or duration of treatment. No mutagenic effect was found. No embryotoxic or teratogenic effects and no effect on fertility reproductive capacity or peri- and postnatal development was shown. 6. Pharmaceutical particulars 6.1 List of excipients Sodium Chloride Ph Eur Water for Injections Ph. Eur Sodium hydroxide or hydrochloric acid for pH adjustment 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 Years. 6.4 Special precautions for storage Store below 25°C. 6.5 Nature and contents of container 1 ml single dose syringe (glass Ph. Eur. Type I) with chlorobutyl rubber stopper containing dalteparin sodium 10,000 IU (anti-Factor Xa) in 1ml solution for injection, Each box contains 5 x 1 ml syringes. 6.6 Special precautions for disposal and other handling Fragmin Graduated Syringes are for single dose use only. 7. Marketing authorisation holder Pfizer Limited Ramsgate Road Sandwich KENT CT13 9NJ United Kingdom 8. Marketing authorisation number(s) PL 00057/0986 9. Date of first authorisation/renewal of the authorisation 29 April 2002 10. Date of revision of the text 02/2013 FR 2_2 ------------------------------------------------ 规格与剂型(本品德国上市包装，购买以咨询为准) 10000iu/0.4ml x5支  10000iu/ml x10支  12500iu/0.5ml x5支  15000iu/0.6ml x5支  18000iu/072ml x5支 25000iu/ml 1支 x 3.8ml   2500iu/0.2ml x10支    5000iu/0.2ml x10支   7500iu/0.3ml x5支 附资料： Fragmin 10,000 IU/0.4ml solution for injection（http://www.medicines.org.uk/emc/medicine/26894） Fragmin 10,000 IU/1 ml（http://www.medicines.org.uk/emc/medicine/26900） Fragmin 10,000 IU/4ml（http://www.medicines.org.uk/emc/medicine/26893） Fragmin 100,000 IU / 4ml Multidose Vial（http://www.medicines.org.uk/emc/medicine/26902） Fragmin 12,500 IU/0.5ml solution for injection（http://www.medicines.org.uk/emc/medicine/26890） Fragmin 15,000 IU/0.6ml solution for injection（http://www.medicines.org.uk/emc/medicine/26891） Fragmin 18,000 IU/0.72ml solution for injection（http://www.medicines.org.uk/emc/medicine/26892） Fragmin 2500 IU（http://www.medicines.org.uk/emc/medicine/26895） Fragmin 5000 IU（http://www.medicines.org.uk/emc/medicine/26896） Fragmin 7,500 IU/0.3 ml solution for injection（http://www.medicines.org.uk/emc/medicine/26897）