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FRAGMIN(dalteparin sodium injection)

——法安明 -急性深静脉血栓的治疗,防止凝血,不稳定型冠心病,预防血栓

2005-03-17 02:13:14 作者：新特药房来源：新特药房药讯浏览次数：151 文字大小：【大】【中】【小】

关键字：达肝素注射液 dalteparin sodium 商标名FRAGMIN 法安明治疗急性深静脉血栓；血液透析

英文药名:FRAGMIN(dalteparin sodium injection)

中文药名:法安明（达肝素注射液）

生产厂家:辉瑞
药品介绍
法安明（达肝素钠）是一种低分子肝素，用于治疗急性深静脉血栓；血液透析和血液过滤期间防止在体外循环系统中发生凝血；不稳定型冠状动脉疾病；预防与手术有关的血栓形成。
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：200 iu/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18000 iu。
每日二次用法：100 iu/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120 iu/kg体重，每日2次，最大剂量为10000 iu/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2500 iu，术后每天早晨皮下注射2500 iu，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5000 iu，术后每晚皮下注射5000 iu，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2500 iu，术后8-12小时皮下注射2500 iu，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1mg鱼精蛋白可抑制100IU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。

The USFDA has approved a new indication for FRAGMIN® (dalteparin sodium injection): extended treatment of symptomatic venous thromboembolism (VTE) [proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE)] to reduce the recurrence of VTE in cancer patients.
In the United States, FRAGMIN is also indicated for the following:
•prevention of DVT, which may lead to PE (pulmonary embolism), in patients undergoing hip replacement surgery, in at- risk patients undergoing abdominal surgery and in at-risk acutely ill patients whose mobility is severely restricted
•prophylaxis of ischemic complications resulting from unstable angina and non- Q-wave myocardial infarction (heart attack), when used with aspirin
Exclusively licensed by Eisai, Inc. from Pfizer, Inc. for U.S. distribution, FRAGMIN® is the first low-molecular- weight heparin (LMWH) approved in the U.S. for the extended treatment of recurrent VTE in patients with cancer.
Fragmin (Dalteparin Sodium) - Description and Clinical Pharmacology
RECENT MAJOR CHANGES
DESCRIPTION
FRAGMIN Injection (dalteparin sodium injection) is a sterile, low molecular weight heparin. It is available in single-dose, prefilled syringes preassembled with a needle guard device, and multiple-dose vials. With reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard, each syringe contains either 2500, 5000, 7500, 10,000, 12,500, 15,000 or 18,000 anti-Factor Xa international units (IU), equivalent to 16, 32, 48, 64, 80, 96 or 115.2 mg dalteparin sodium, respectively. Each multiple-dose vial contains either 10,000 or 25,000 anti-Factor Xa IU per 1 mL (equivalent to 64 or 160 mg dalteparin sodium, respectively), for a total of 95,000 anti-Factor Xa IU per vial.
Each prefilled syringe also contains Water for Injection and sodium chloride, when required, to maintain physiologic ionic strength. The prefilled syringes are preservative-free. Each multiple-dose vial also contains Water for Injection and 14 mg of benzyl alcohol per mL as a preservative. The pH of both formulations is 5.0 to 7.5. [See Dosage and Administration (2) and How Supplied (16)]
Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. It is composed of strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5000 and about 90% of the material within the range 2000-9000. The molecular weight distribution is:
    < 3000 daltons    3.0-15%
    3000 to 8000 daltons    65.0-78.0%
    > 8000 daltons    14.0-26.0%
STRUCTURAL FORMULA

CLINICAL PHARMACOLOGY
Mechanism of Action
Dalteparin is a low molecular weight heparin with antithrombotic properties. It acts by enhancing the inhibition of Factor Xa and thrombin by antithrombin. In humans, dalteparin potentiates preferentially the inhibition of coagulation Factor Xa, while only slightly affecting the activated partial thromboplastin time (APTT).
Pharmacodynamics
Doses of FRAGMIN Injection of up to 10,000 anti-Factor Xa IU administered subcutaneously as a single dose or two 5000 IU doses 12 hours apart to healthy subjects did not produce a significant change in platelet aggregation, fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin time (TT) or APTT. Subcutaneous administration of doses of 5000 IU twice daily of FRAGMIN for seven consecutive days to patients undergoing abdominal surgery did not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.
Pharmacokinetics
Mean peak levels of plasma anti-Factor Xa activity following single subcutaneous doses of 2500, 5000 and 10,000 IU were 0.19 ± 0.04, 0.41 ± 0.07 and 0.82 ± 0.10 IU/mL, respectively, and were attained in about 4 hours in most subjects. Absolute bioavailability in healthy volunteers, measured as the anti-Factor Xa activity, was 87 ± 6%. Increasing the dose from 2500 to 10,000 IU resulted in an overall increase in anti-Factor Xa AUC that was greater than proportional by about one-third.
Peak anti-Factor Xa activity increased more or less linearly with dose over the same dose range. There appeared to be no appreciable accumulation of anti-Factor Xa activity with twice-daily dosing of 100 IU/kg subcutaneously for up to 7 days.
The volume of distribution for dalteparin anti-Factor Xa activity was 40 to 60 mL/kg. The mean plasma clearances of dalteparin anti-Factor Xa activity in normal volunteers following single intravenous bolus doses of 30 and 120 anti-Factor Xa IU/kg were 24.6 ± 5.4 and 15.6 ± 2.4 mL/hr/kg, respectively. The corresponding mean disposition half-lives were 1.47 ± 0.3 and 2.5 ± 0.3 hours.
Following intravenous doses of 40 and 60 IU/kg, mean terminal half-lives were 2.1 ± 0.3 and 2.3 ± 0.4 hours, respectively. Longer apparent terminal half-lives (3 to 5 hours) are observed following subcutaneous dosing, possibly due to delayed absorption. In patients with chronic renal insufficiency requiring hemodialysis, the mean terminal half-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU FRAGMIN 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Dalteparin sodium has not been tested for its carcinogenic potential in long-term animal studies. It was not mutagenic in the in vitro Ames Test, mouse lymphoma cell forward mutation test and human lymphocyte chromosomal aberration test and in the in vivo mouse micronucleus test. Dalteparin sodium at subcutaneous doses up to 1200 IU/kg (7080 IU/m2) did not affect the fertility or reproductive performance of male and female rats.
CLINICAL STUDIES
Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
In a double-blind, randomized, placebo-controlled clinical trial, patients who recently experienced unstable angina with EKG changes or non-Q-wave myocardial infarction (MI) were randomized to FRAGMIN Injection 120 IU/kg or placebo every 12 hours subcutaneously. In this trial, unstable angina was defined to include only angina with EKG changes. All patients, except when contraindicated, were treated concurrently with aspirin (75 mg once daily) and beta blockers. Treatment was initiated within 72 hours of the event (the majority of patients received treatment within 24 hours) and continued for 5 to 8 days. A total of 1506 patients were enrolled and treated; 746 received FRAGMIN and 760 received placebo. The mean age of the study population was 68 years (range 40 to 90 years) and the majority of patients were white (99.7%) and male (63.9%). The combined incidence of the endpoint of death or myocardial infarction was lower for FRAGMIN compared with placebo at 6 days after initiation of therapy. These results were observed in an analysis of all-randomized and all-treated patients. The combined incidence of death, MI, need for intravenous heparin or intravenous. nitroglycerin, and revascularization was also lower for FRAGMIN than for placebo (see Table 10).

Table 10

Efficacy of FRAGMIN in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

Indication Dosing Regimen

FRAGMIN
120 IU/kg/every 12 hr subcutaneous
n (%) Placebo
every 12 hr subcutaneous
n (%)

All Treated Unstable Angina and Non-Q-Wave MI Patients 746 760

Primary Endpoints - 6 day timepoint
Death, MI 13/741 (1.8)¹ 36/757 (4.8)

Secondary Endpoints - 6 day timepoint
Death, MI, intravenous heparin, i.v. nitroglycerin, Revascularization 59/739 (8.0)¹ 106/756 (14.0)
1 p-value = 0.001
In a second randomized, controlled trial designed to evaluate long-term treatment with FRAGMIN (days 6 to 45), data were also collected comparing 1-week (5 to 8 days) treatment of FRAGMIN 120 IU/kg every 12 hours subcutaneously with heparin at an APTT-adjusted dosage. All patients, except when contraindicated, were treated concurrently with aspirin (100 to 165 mg per day). Of the 1499 patients enrolled, 1482 patients were treated; 751 received FRAGMIN and 731 received heparin. The mean age of the study population was 64 years (range 25 to 92 years) and the majority of patients were white (96.0%) and male (64.2%). The incidence of the combined endpoint of death, myocardial infarction, or recurrent angina during this 1-week treatment period (5 to 8 days) was 9.3% for FRAGMIN and 7.6% for heparin (p=0.323).
Prophylaxis of Deep Vein Thrombosis in Patients Following Hip Replacement Surgery
In an open-label randomized study, FRAGMIN 5000 IU administered once daily subcutaneously was compared with warfarin sodium, administered orally, in patients undergoing hip replacement surgery. Treatment with FRAGMIN was initiated with a 2500 IU dose subcutaneously within 2 hours before surgery, followed by a 2500 IU dose subcutaneously the evening of the day of surgery. Then, a dosing regimen of FRAGMIN 5000 IU subcutaneously once daily was initiated on the first postoperative day. The first dose of warfarin sodium was given the evening before surgery, then continued daily at a dose adjusted for INR 2 to 3. Treatment in both groups was then continued for 5 to 9 days postoperatively. Of the 580 patients enrolled, 553 were treated and 550 underwent surgery. Of those who underwent surgery, 271 received FRAGMIN and 279 received warfarin sodium. The mean age of the study population was 63 years (range 20 to 92 years) and the majority of patients were white (91.1%) and female (52.9%). The incidence of deep vein thrombosis (DVT), as determined by evaluable venography, was significantly lower for the group treated with FRAGMIN compared with patients treated with warfarin sodium (see Table 11).

Table 11

Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery

Indication Dosing Regimen

FRAGMIN
5000 IU once daily¹ subcutaneous
n (%) Warfarin Sodium
once daily² oral
n (%)

All Treated Hip Replacement Surgery Patients 271 279

Treatment Failures in Evaluable Patients
DVT, Total 28/192 (14.6)³ 49/190 (25.8)

Proximal DVT 10/192 (5.2)⁴ 16/190 (8.4)

PE 2/271 (0.7) 2/279 (0.7)
1 The daily dose on the day of surgery was divided: 2500 IU was given two hours before surgery and again in the evening of the day of surgery.
2 Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of approximately 2.5
3 p-value = 0.006
4 p-value = 0.185
In a second single-center, double-blind study of patients undergoing hip replacement surgery, FRAGMIN 5000 IU once daily subcutaneously starting the evening before surgery, was compared with heparin 5000 U subcutaneously three times a day, starting the morning of surgery. Treatment in both groups was continued for up to 9 days postoperatively. Of the 140 patients enrolled, 139 were treated and 136 underwent surgery. Of those who underwent surgery, 67 received FRAGMIN and 69 received heparin. The mean age of the study population was 69 years (range 42 to 87 years) and the majority of patients were female (58.8%). In the intent-to-treat analysis, the incidence of proximal DVT was significantly lower for patients treated with FRAGMIN compared with patients treated with heparin (6/67 vs 18/69; p=0.012). The incidence of pulmonary embolism detected by lung scan was also significantly lower in the group treated with FRAGMIN (9/67 vs 19/69; p=0.032).
A third multi-center, double-blind, randomized study evaluated a postoperative dosing regimen of FRAGMIN for thromboprophylaxis following total hip replacement surgery. Patients received either FRAGMIN or warfarin sodium, randomized into one of three treatment groups. One group of patients received the first dose of FRAGMIN 2500 IU subcutaneous within 2 hours before surgery, followed by another dose of FRAGMIN 2500 IU subcutaneous at least 4 hours (6.6 ± 2.3 hr) after surgery. Another group received the first dose of FRAGMIN 2500 IU subcutaneous at least 4 hours (6.6 ± 2.4 hr) after surgery. Then, both of these groups began a dosing regimen of FRAGMIN 5000 IU once daily subcutaneous on postoperative day 1. The third group of patients received warfarin sodium the evening of the day of surgery, then continued daily at a dose adjusted to maintain INR 2 to 3. Treatment for all groups was continued for 4 to 8 days postoperatively, after which time all patients underwent bilateral venography.
In the total enrolled study population of 1501 patients, 1472 patients were treated; 496 received FRAGMIN (first dose before surgery), 487 received FRAGMIN (first dose after surgery) and 489 received warfarin sodium. The mean age of the study population was 63 years (range 18 to 91 years) and the majority of patients were white (94.4%) and female (51.8%).
Administration of the first dose of FRAGMIN after surgery was as effective in reducing the incidence of thromboembolic reactions as administration of the first dose of FRAGMIN before surgery (44/336 vs 37/338; p=0.448). Both dosing regimens of FRAGMIN were more effective than warfarin sodium in reducing the incidence of thromboembolic reactions following hip replacement surgery.
Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications
Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes, or who have additional risk factors such as malignancy or a history of deep vein thrombosis or pulmonary embolism.
FRAGMIN administered once daily subcutaneously beginning prior to surgery and continued for 5 to 10 days after surgery, reduced the risk of DVT in patients at risk for thromboembolic complications in two double-blind, randomized, controlled clinical trials performed in patients undergoing major abdominal surgery. In the first study, a total of 204 patients were enrolled and treated; 102 received FRAGMIN and 102 received placebo. The mean age of the study population was 64 years (range 40 to 98 years) and the majority of patients were female (54.9%). In the second study, a total of 391 patients were enrolled and treated; 195 received FRAGMIN and 196 received heparin. The mean age of the study population was 59 years (range 30 to 88 years) and the majority of patients were female (51.9%). FRAGMIN 2500 IU was superior to placebo and similar to heparin in reducing the risk of DVT (see Tables 12 and 13).

Table 12

Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery

Indication Dosing Regimen

FRAGMIN
2500 IU once daily subcutaneous
n (%) Placebo
once daily subcutaneous
n (%)

All Treated Abdominal Surgery Patients 102 102

Treatment Failures in Evaluable Patients
  Total Thromboembolic Reactions 4/91 (4.4)¹ 16/91 (17.6)

     Proximal DVT 0 5/91 (5.5)

     Distal DVT 4/91 (4.4) 11/91 (12.1)

  PE 0 2/91 (2.2)2

¹  p-value = 0.74

Table 13

Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery

Indication Dosing Regimen

FRAGMIN
2500 IU once daily subcutaneous
n (%) Heparin
5000 U twice daily subcutaneous
n (%)

All Treated Abdominal Surgery Patients 195 196

Treatment Failures in Evaluable Patients
  Total Thromboembolic Reactions 7/178 (3.9)¹ 7/174 (4.0)

     Proximal DVT 3/178 (1.7) 4/174 (2.3)

     Distal DVT 3/178 (1.7) 3/174 (1.7)

  PE 1/178 (0.6) 0
In a third double-blind, randomized study performed in patients undergoing major abdominal surgery with malignancy, FRAGMIN 5000 IU subcutaneous once daily was compared with FRAGMIN 2500 IU subcutaneous once daily. Treatment was continued for 6 to 8 days. A total of 1375 patients were enrolled and treated; 679 received FRAGMIN 5000 IU and 696 received 2500 IU. The mean age of the combined groups was 71 years (range 40 to 95 years). The majority of patients were female (51.0%). FRAGMIN 5000 IU once daily was more effective than FRAGMIN 2500 IU once daily in reducing the risk of DVT in patients undergoing abdominal surgery with malignancy (see Table 14).

Table 14

Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery

Indication Dosing Regimen

FRAGMIN
2500 IU once daily subcutaneous
n (%) FRAGMIN
5000 IU once daily subcutaneous
n (%)

All Treated Abdominal Surgery Patients¹ 696 679

Treatment Failures in Evaluable Patients
  Total Thromboembolic Reactions 99/656 (15.1)² 60/645 (9.3)

     Proximal DVT 18/657 (2.7) 14/646 (2.2)

     Distal DVT 80/657 (12.2) 41/646 (6.3)

  PE

     Fatal 1/674 (0.1) 1/669 (0.1)

     Non-fatal 2 4
Prophylaxis of Deep Vein Thrombosis in Medical Patients at Risk for Thromboembolic Complications Due to Severely Restricted Mobility During Acute Illness
In a double-blind, multi-center, randomized, placebo-controlled clinical trial, general medical patients with severely restricted mobility who were at risk of venous thromboembolism were randomized to receive either FRAGMIN 5000 IU or placebo subcutaneously once daily during Days 1 to 14 of the study. These patients had an acute medical condition requiring a projected hospital stay of at least 4 days, and were confined to bed during waking hours. The study included patients with congestive heart failure (NYHA Class III or IV), acute respiratory failure not requiring ventilatory support, and the following acute conditions with at least one risk factor occurring in > 1% of treated patients: acute infection (excluding septic shock), acute rheumatic disorder, acute lumbar or sciatic pain, vertebral compression, or acute arthritis of the lower extremities. Risk factors include > 75 years of age, cancer, previous DVT/PE, obesity and chronic venous insufficiency. A total of 3681 patients were enrolled and treated: 1848 received FRAGMIN and 1833 received placebo. The mean age of the study population was 69 years (range 26 to 99 years), 92.1% were white and 51.9% were female. The primary efficacy endpoint was evaluated at Day 21 and was defined as at least one of the following within Days 1 to 21 of the study: asymptomatic DVT (diagnosed by compression ultrasound), a confirmed symptomatic DVT, a confirmed pulmonary embolism or sudden death. The follow-up extended through Day 90
When given at a dose of 5000 IU once a day subcutaneously, FRAGMIN significantly reduced the incidence of thromboembolic reactions including verified DVT by Day 21 (see Table 15). The prophylactic effect was sustained through Day 90.

Table 15

Efficacy of FRAGMIN in the Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility During Acute Illness

Indication Dosing Regimen

FRAGMIN
5000 IU once daily subcutaneous
n (%) Placebo
once daily subcutaneous
n (%)

All Treated Medical Patients
During Acute Illness 1848 1833

Treatment failure in evaluable patients (Day 21)¹
  DVT, PE, or sudden death 42/1518 (2.8)² 73/1473 (5.0)

Total Thromboembolic Reactions (Day 21) 37/1513 (2.5) 70/1470 (4.8)

Total DVT 32/1508 (2.1) 64/1464 (4.4)

Proximal DVT 29/1518 (1.9) 60/1474 (4.1)

Symptomatic VTE 10/1759 (0.6) 17/1740 (1.0)

PE 5/1759 (0.3) 6/1740 (0.3)

Sudden Death 5/1829 (0.3) 3/1807 (0.2)
Patients with Cancer and Acute Symptomatic Venous Thromboembolism
In a prospective, multi-center, open-label, clinical trial, 676 patients with cancer and newly diagnosed, objectively confirmed acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were studied. Patients were randomized to either FRAGMIN 200 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for one month) then 150 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for five months (FRAGMIN arm) or FRAGMIN 200 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for five to seven days and oral anticoagulant for six months (OAC arm). In the OAC arm, oral anticoagulation was adjusted to maintain an INR of 2 to 3. Patients were evaluated for recurrence of symptomatic venous thromboembolism (VTE) every two weeks for six months.
The median age of patients was 64 years (range: 22 to 89 years); 51.5% of patients were females; 95.3% of patients were Caucasians. Types of tumors were: gastrointestinal tract (23.7%), genito-urinary (21.5%), breast (16%), lung (13.3%), hematological tumors (10.4%) and other tumors (15.1%).
A total of 27 (8.0%) and 53 (15.7%) patients in the FRAGMIN and OAC arms, respectively, experienced at least one episode of an objectively confirmed, symptomatic DVT and/or PE during the 6-month study period. Most of the difference occurred during the first month of treatment (see Table 16). The benefit was maintained over the 6-month study period.

Table 16

Recurrent VTE in Patients with Cancer (Intention to treat population)¹

Study Period FRAGMIN arm OAC arm

FRAGMIN 200 IU/kg (max. 18,000 IU) subcutaneous once daily x 1 month, then 150 IU/kg (max. 18,000 IU) subcutaneous once daily x 5 months FRAGMIN 200 IU/kg (max 18,000 IU) subcutaneous once daily x 5-7 days and OAC for 6 months (target INR 2-3)

Number at Risk Patients with VTE % Number at Risk Patients with VTE %

Total 338 27 8.0 338 53 15.7

Week 1 338 5 1.5 338 8 2.4

Weeks 2-4 331 6 1.8 327 25 7.6

Weeks 5-28 307 16 5.2 284 20 7.0
In the intent-to-treat population that included all randomized patients, the primary comparison of the cumulative probability of the first VTE recurrence over the 6-month study period was statistically significant (p < 0.01) in favor of the FRAGMIN arm, with most of the treatment difference evident in the first month.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c5cd4a8e-14c0-440b-b453-9f3d3250c951

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FRAGMIN 10000IU/1.0ML PFS 10/PAC DALTEPARIN SODIUM     62856-0101-10
FRAGMIN 12500IU/0.5ML PFS 10/PAC DALTEPARIN SODIUM     62856-0125-10
FRAGMIN 15000IU/0.6ML PFS 10/PAC DALTEPARIN SODIUM     62856-0150-10
FRAGMIN 18000IU/0.72ML PFS 10/PAC DALTEPARIN SODIUM     62856-0180-10
FRAGMIN 25000IU/ML 3.8ML MDV 1/EA DALTEPARIN SODIUM     62856-0251-01
FRAGMIN 5000IU/0.2ML PFS 10/PAC DALTEPARIN SODIUM     62856-0500-10
FRAGMIN 7500IU/0.3ML PFS 10/PAC DALTEPARIN SODIUM     62856-0750-10
FRAGMIN MDV 25000IU/ML 3.8ML DALTEPARIN SODIUM PORCINE     62856-0251-01
FRAGMIN PFS 10000IU/ML 1ML 10 DALTEPARIN SODIUM PORCINE     62856-0101-10
FRAGMIN PFS 12500IU/0.5ML 10 DALTEPARIN SODIUM PORCINE     62856-0125-10
FRAGMIN PFS 18000IU/0.72ML 10 DALTEPARIN SODIUM PORCINE     62856-0180-10
FRAGMIN PFS 2500IU/0.2ML 10 DALTEPARIN SODIUM PORCINE     62856-0250-10
FRAGMIN PFS 5000IU/0.2ML 10 DALTEPARIN SODIUM PORCINE     62856-0500-10
FRAGMIN PFS 7500IU/0.3ML 10 DALTEPARIN SODIUM PORCINE     62856-0750-10
FRAGMIN 5000IU/0.2ML PFS 10/PAC DALTEPARIN SODIUM     00069-0196-02
FRAGMIN 7500IU/0.3ML PFS 10/PAC DALTEPARIN SODIUM     00069-0206-02
FRAGMIN 10000IU/1.0ML PFS 10/PAC DALTEPARIN SODIUM     00069-0217-02
FRAGMIN 12500IU/0.5ML PFS 10/PAC DALTEPARIN SODIUM     00069-0220-02
FRAGMIN 15000IU/0.6ML PFS 10/PAC DALTEPARIN SODIUM     00069-0223-02
FRAGMIN 18000IU/0.72ML PFS 10/PAC DALTEPARIN SODIUM     00069-0228-02
FRAGMIN PFS 12500IU/.5ML 10 DALTEPARIN SODIUM PORCINE     00069-0220-02
FRAGMIN PFS 15000IU/.6ML 10 DALTEPARIN SODIUM PORCINE     00069-0223-02
FRAGMIN PFS 2500IU/0.2ML 10 DALTEPARIN SODIUM PORCINE     00069-0195-02
FRAGMIN PFS 5000IU/0.2ML 10 DALTEPARIN SODIUM PORCINE     00069-0196-02
FRAGMIN PFS 7500IU/0.3ML 10 DALTEPARIN SODIUM PORCINE     00069-0206-02
FRAGMIN MDV 25000IU/ML 3.8ML DALTEPARIN SODIUM PORCINE     00069-0232-01
FRAGMIN PFS 10000 IU/1ML 10 DALTEPARIN SODIUM PORCINE     00069-0217-02
FRAGMIN PFS 15000IU/0.6ML 10 DALTEPARIN SODIUM PORCINE     62856-0150-10
FRAGMIN PFS18000IU/.72ML 10 DALTEPARIN SODIUM PORCINE     00069-0228-02