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Fragmin

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Fragmin

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 (dalteparin) 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 (dalteparin) 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 (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.

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 (dalteparin) 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 (dalteparin) 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 (dalteparin) 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 (dalteparin) than for placebo (see Table 10).

Table 10 : Efficacy of FRAGMIN (dalteparin) in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

Indication Dosing Regimen
FRAGMIN (dalteparin) 120 IU/kg/every 12 hr subcutaneous
n (%)
Placebo every12 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 (dalteparin) (days 6 to 45), data were also collected comparing 1-week (5 to 8 days) treatment of FRAGMIN (dalteparin) 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 (dalteparin) 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 (dalteparin) 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 (dalteparin) 5000 IU administered once daily subcutaneously was compared with warfarin sodium, administered orally, in patients undergoing hip replacement surgery. Treatment with FRAGMIN (dalteparin) 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 (dalteparin) 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 (dalteparin) 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 (dalteparin) compared with patients treated with warfarin sodium (see Table 11).

Table 11 : Efficacy of FRAGMIN (dalteparin) in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery

Indication Dosing Regimen
FRAGMIN (dalteparin) 5000 IU once daily1 subcutaneous
n (%)
Warfarin Sodium once daily 2 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 (dalteparin) 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 (dalteparin) 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 (dalteparin) 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 (dalteparin) (9/67 vs 19/69; p=0.032).

A third multi-center, double-blind, randomized study evaluated a postoperative dosing regimen of FRAGMIN (dalteparin) for thromboprophylaxis following total hip replacement surgery. Patients received either FRAGMIN (dalteparin) or warfarin sodium, randomized into one of three treatment groups. One group of patients received the first dose of FRAGMIN (dalteparin) 2500 IU subcutaneous within 2 hours before surgery, followed by another dose of FRAGMIN (dalteparin) 2500 IU subcutaneous at least 4 hours (6.6 ± 2.3 hr) after surgery. Another group received the first dose of FRAGMIN (dalteparin) 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 (dalteparin) 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 (dalteparin) (first dose before surgery), 487 received FRAGMIN (dalteparin) (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 (dalteparin) after surgery was as effective in reducing the incidence of thromboembolic reactions as administration of the first dose of FRAGMIN (dalteparin) before surgery (44/336 vs 37/338; p=0.448). Both dosing regimens of FRAGMIN (dalteparin) 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 (dalteparin) 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 (dalteparin) 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 (dalteparin) 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 (dalteparin) 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 (dalteparin) in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery

Indication Dosing Regimen
FRAGMIN (dalteparin) 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 = 0.008
2 Both patients also had DVT, 1 proximal and 1 distal

Table 13 : Efficacy of FRAGMIN (dalteparin) in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery

Indication Dosing Regimen
FRAGMIN (dalteparin) 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
1 p-value = 0.74

In a third double-blind, randomized study performed in patients undergoing major abdominal surgery with malignancy, FRAGMIN (dalteparin) 5000 IU subcutaneous once daily was compared with FRAGMIN (dalteparin) 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 (dalteparin) 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 (dalteparin) 5000 IU once daily was more effective than FRAGMIN (dalteparin) 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 (dalteparin) in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery

Indication Dosing Regimen
FRAGMIN (dalteparin) 2500 IU once daily subcutaneous
n (%)
FRAGMIN (dalteparin) 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
1 Major abdominal surgery with malignancy
2 p-value = 0.001

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 (dalteparin) 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 (dalteparin) 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 (dalteparin) 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 (dalteparin) in the Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility During Acute Illness

Indication Dosing Regimen
FRAGMIN (dalteparin) 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)
1 Defined as DVT (diagnosed by compression ultrasound at Day 21 + 3), confirmed symptomatic DVT, confirmed PE or sudden death. 22 p-value = 0.0015

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 (dalteparin) 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 (dalteparin) arm) or FRAGMIN (dalteparin) 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 (dalteparin) 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
1 Three patients in the FRAGMIN arm and 5 patients in the OAC arm experienced more than 1 VTE over the 6-month study period.

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 6month study period was statistically significant (p < 0.01) in favor of the FRAGMIN (dalteparin) arm, with most of the treatment difference evident in the first month.

Last reviewed on RxList: 12/2/2010
This monograph has been modified to include the generic and brand name in many instances.

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