VA Class:BL110

AHFS Class:

• Heparins 20:12.04.16

Generic Name(s):

• Dalteparin Sodium

Chemical Name:

• Heparin, sodium salt

Dalteparin sodium, a low molecular weight heparin prepared by nitrous acid degradation of heparin (referring throughout this monograph to unfractionated heparin) of porcine intestinal mucosa origin, is an anticoagulant.1,3,5,10,22,23,26

Dalteparin is used concurrently with aspirin and/or other therapy (e.g., nitrates, β-adrenergic blockers, P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonists [e.g., clopidogrel, prasugrel, ticagrelor], platelet glycoprotein [GP] IIb/IIIa-receptor inhibitors) to reduce the risk of acute cardiac ischemic events (death and/or myocardial infarction [MI]) in patients with unstable angina or non-ST-segment-elevation myocardial infarction (NSTEMI) (i.e., non-ST-segment-elevation acute coronary syndromes [NSTE ACS]).1,51,52,53,54,66,103,104,991 Dalteparin also is used for the prevention of deep-vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing hip-replacement surgery, patients undergoing general/abdominal (e.g., GI, gynecologic, urologic) surgery, and in patients with acute medical conditions (e.g., cancer, bedrest, heart failure, severe lung disease) and severely restricted mobility who are at risk for thromboembolic complications.1,3,6,7,8,9,10,19,20,21,22,60,63,64,1001,1002,1003

The use of a low molecular weight heparin such as dalteparin also is suggested by the American College of Chest Physicians (ACCP) as first-line or alternative therapy for prevention of venous thromboembolism in selected patients undergoing intracranial neurologic surgery† or spinal surgery†; in patients with major trauma†, including brain injury, acute spinal injury, and traumatic spine injury; selected cancer patients; and in patients with acute ischemic stroke†.125,1001,1002,1009 Therapy with a low molecular weight heparin also has been recommended in selected patients for prevention of embolism associated with atrial fibrillation or atrial flutter†97,98,154,999,1017 or thromboembolism associated with prosthetic heart valves†996 and for prevention or treatment of thromboembolism during pregnancy†.1012,1017 Although a causal relationship has not been established and the number of patients involved appears to be small, cases of valve thrombosis resulting in death (including maternal and fetal deaths) and/or requiring surgical intervention have been reported with at least one low molecular weight heparin (enoxaparin) during thromboprophylaxis in some patients (including pregnant women) with prosthetic heart valves; insufficient data, underlying conditions, and the possibility of inadequate anticoagulation also complicate evaluation of these events.101,107,108,109,110,111,112,113,114,115,996,1012 However, ACCP suggests that in the absence of definitive data regarding optimal therapy in pregnant patients with prosthetic heart valves† and the associated risks of withholding antithrombotic therapy, use of a low molecular weight heparin at a dosage adjusted to maintain the manufacturer-recommended peak anti-factor Xa concentrations 4 hours postinjection appears reasonable in such patients.996,1012 (See Uses: Thromboembolism Associated with Prosthetic Heart Valves, in Enoxaparin 20:12.04.16.) The manufacturer of dalteparin states that the drug has not been studied systematically in patients with prosthetic heart valves†.102 For further details on the use of low molecular weight heparins in various thromboembolic conditions, see Uses in Enoxaparin 20:12.04.16.

The usual precautions and contraindications associated with heparin anticoagulation should be followed in patients for whom dalteparin therapy is considered.1 (See Cautions.)

Unstable Angina and Non-ST-Segment-Elevation Myocardial Infarction

Dalteparin is used concurrently with aspirin and/or other standard therapy (e.g., nitrates, β-adrenergic blockers, a P2Y12 platelet ADP-receptor antagonist [e.g., clopidogrel, prasugrel, ticagrelor], GP IIb/IIIa-receptor inhibitors) to reduce the risk of acute cardiac ischemic events (death and/or MI) in patients with unstable angina or NSTEMI ([NSTE ACS]).1,51,52,53,54,66,103,104,991

If a low molecular weight heparin is selected for initial parenteral anticoagulation in patients with NSTE ACS, the American Heart Association (AHA) and American College of Cardiology Foundation (ACCF) guidelines recommend the use of enoxaparin; other parenteral anticoagulants with established efficacy include heparin, bivalirudin (only in patients who are being managed with an early invasive strategy), and fondaparinux.1100

In several large placebo-controlled trials (Fragmin during Instability in Coronary Artery Disease [FRISC], Fragmin and Fast Revascularization during Instability in Coronary Artery Disease [FRISC II]) in patients who recently experienced unstable angina or NSTEMI (within 48-72 hours of treatment), therapy with dalteparin sodium (120 units/kg every 12 hours subcutaneously for 5-6 days followed by 5000-7500 units once or twice daily for 1.5-3 months) reduced the combined incidence of death or nonfatal MI (Q-wave MI) at 6 and 30 days.1,51,52 However, when a secondary end point was included, the need for revascularization after 40 days, the reduction in the frequency of the combined outcome of death, nonfatal MI, and need for revascularization persisted with dalteparin compared with placebo but was apparent only in nonsmokers (80% of the sample).51,52 Patients in the FRISC trial included those with acute coronary syndromes at low to high risk of ischemic complications; patients in the FRISC II trial included those at intermediate to high risk for ischemic complications, including those undergoing PCI.50,51,52

All patients in clinical trials of dalteparin for NSTE ACS received concomitant therapy with aspirin;1,51,52,53,54 the benefit of aspirin for secondary prevention of ischemic events in patients with unstable angina has been demonstrated in several studies and pooled analyses of data.55,56

Deep-Vein Thrombosis and/or Pulmonary Embolism

Prophylaxis

Hip-Replacement, Knee-Replacement, or Hip-Fracture Surgery

Dalteparin is used for the prevention of DVT, which may lead to PE, in patients undergoing hip-replacement surgery.1,60,63,64,1003 Low molecular weight heparins also have been used for thromboprophylaxis in patients undergoing other types of major orthopedic procedures such as total knee-replacement† and hip-fracture surgery†.1003 ACCP recommends routine thromboprophylaxis (with a pharmacologic and/or mechanical [e.g., intermittent pneumatic compression] method) in all patients undergoing major orthopedic surgery, including total hip-replacement, total knee-replacement, and hip-fracture surgery, because of the high risk for postoperative venous thromboembolism; thromboprophylaxis should be continued for at least 10-14 days, and possibly for up to 35 days after surgery.1003 Several antithrombotic agents (e.g., low molecular weight heparins, fondaparinux, low-dose heparin, warfarin, aspirin) are recommended by ACCP for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery.1003 Among the different options, ACCP suggests that a low molecular weight heparin generally is preferred because of its relative efficacy and safety and extensive clinical experience; alternative agents may be considered in situations in which a low molecular weight heparin is not available or cannot be used (e.g., in patients with heparin-induced thrombocytopenia [HIT] or in those who refuse or are uncooperative with subcutaneous injections).1003 ACCP states that when selecting an appropriate thromboprophylaxis regimen, factors such as relative efficacy and bleeding risk as well as logistics and compliance issues should be considered.1003 For additional information on the prevention of venous thromboembolism in patients undergoing major orthopedic surgery, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web].

Data from several comparative clinical trials indicate that dalteparin is more effective than warfarin in preventing thromboembolic events in patients undergoing hip-replacement surgery.1,60,63 In a comparative short-term study (beginning preoperatively and continued for up to 9 days postoperatively) in patients undergoing hip-replacement surgery and receiving thromboprophylaxis with dalteparin sodium (2500 units subcutaneously 2 hours preoperatively followed by 2500 units on the evening of surgery, then 5000 units once daily on the first and subsequent postoperative days) or warfarin (5-7.5 mg on the evening before and after surgery followed by a daily dosage adjusted to achieve a target international normalized ratio [INR] of 2.5), postoperative DVT or proximal DVT (determined by venography) occurred in 15 or 5% of patients treated with dalteparin versus 26 or 8% of patients treated with warfarin, respectively.1,63 The incidence of PE was similar in each treatment group.1 In another short-term study (duration of therapy 4-8 days postoperatively) in patients undergoing hip-replacement surgery who received either preoperative dalteparin (within 2 hours before surgery), postoperative dalteparin (at least 4 hours after surgery), or postoperative warfarin, initiation of dalteparin at either time was more effective than warfarin (dosage adjusted to maintain an INR of 2-3) in preventing DVT or proximal DVT (as determined by venography).60 In addition, symptomatic DVT occurred less frequently in patients treated with preoperative dalteparin than with warfarin.60

In another short-term comparative study (therapy beginning preoperatively and continuing for up to 9 days postoperatively) with dalteparin sodium (5000 units initiated the evening before surgery and once daily thereafter) and subcutaneous, fixed low-dose heparin sodium (5000 units 3 times daily, initiated 2 hours preoperatively), the incidence of DVT was similar in both treatment groups.64 The incidence of proximal (thigh) DVT and PE was lower in patients receiving dalteparin than in those receiving low-dose heparin.1,64

Some evidence suggests that extended prophylaxis† with a low molecular weight heparin (i.e., for up to 35 days post-surgery) may provide additional protection against thromboembolism in patients undergoing total hip- or total knee-replacement surgery† .1003 While the manufacturer states that the usual duration of dalteparin therapy following hip-replacement surgery is 5-10 days, with administration for up to 14 days in clinical trials,1 ACCP suggests extended prophylaxis for up to 35 days in patients undergoing major orthopedic surgery.1003

General/Abdominal Surgery

Dalteparin is used for the prevention of postoperative DVT, which may lead to PE, in patients undergoing general/abdominal surgery who are at risk for thromboembolic complications.1,3,6,7,8,9,10,19,20,21,22,1002 According to the manufacturer, abdominal surgery patients who are considered to be at risk for thromboembolic complications include individuals who are 40 years of age or older, obese, or undergoing major surgical procedures (defined as surgery requiring general anesthesia that exceeds 30 minutes in duration) and those with additional risk factors such as malignancy or a history of DVT or PE;1 however, other risk factors also may apply depending on the risk stratification method used.1002 In general, clinicians should consider a combination of patient- and procedure-specific factors when determining a patient's level of risk of thromboembolism.1002

ACCP recommends pharmacologic (e.g., a low molecular weight heparin) and/or nonpharmacologic/mechanical (e.g., intermittent pneumatic compression) methods of thromboprophylaxis in patients undergoing general and abdominal-pelvic surgery, including GI, gynecologic, and urologic surgery, according to the patient's level of risk for thromboembolism and bleeding.1002 Pharmacologic prophylaxis generally is recommended in patients with high (and possibly moderate) risk of venous thromboembolism who do not have a high risk of bleeding, while mechanical methods are suggested in patients who require thromboprophylaxis but have a high risk of bleeding.1002 If pharmacologic thromboprophylaxis is used in patients undergoing general and abdominal-pelvic surgery, ACCP states that a low molecular weight heparin or low-dose heparin is preferred; however, when these agents are contraindicated or not available, aspirin or fondaparinux may be considered.1002 Because the risk of venous thromboembolism is particularly high in patients undergoing abdominal or pelvic surgery for cancer, extended (4 weeks) prophylaxis with a low molecular weight heparin is recommended in such patients.1002 ACCP states that the same recommendations for the use of antithrombotic agents in general and abdominal-pelvic surgery patients can be applied to patients undergoing bariatric surgery, vascular surgery, and plastic and reconstructive surgery.1002 For additional information on the prevention of venous thromboembolism in patients undergoing general and abdominal-pelvic surgery, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web].

Based on indirect evidence from patients undergoing general surgery, use of thromboprophylaxis following cesarean section may be beneficial in patients with additional risk factors (e.g., immobility, previous thromboembolic event, thrombophilia) for venous thromboembolism.1012 If pharmacologic prophylaxis is used in patients undergoing cesarean section, ACCP states that a low molecular heparin generally is preferred over heparin because of its favorable safety profile.1012

In a placebo-controlled, double-blind study in patients at risk for thromboembolic complications undergoing major abdominal surgery in whom prophylaxis was initiated 1-2 hours prior to surgery and continued for 5-10 days, thromboembolic events (i.e., proximal or distal DVT detected by radioisotope leg scan and/or PE detected by perfusion lung scan) occurred in 4.4% of patients treated with dalteparin sodium 2500 units daily versus 17.6% of placebo-treated patients.1,6 Dalteparin was particularly effective in reducing the incidence of venous thrombosis in patients undergoing surgery for malignant disease.6 Comparative studies indicate that subcutaneous dalteparin sodium (2500 units daily) is at least as effective as subcutaneous heparin sodium (5000 units twice daily) in preventing thromboembolic events in at-risk patients undergoing abdominal surgery.1,7,8,9,29 In one study, thromboembolic events occurred in 3.9 or 4% of patients receiving these dosages of dalteparin or heparin, respectively.1,8

There is some evidence that efficacy of dalteparin is dose dependent.1,33 In one study, dalteparin sodium 5000 units daily was more effective in preventing thrombotic complications than dalteparin sodium 2500 units daily in patients undergoing abdominal surgery for malignant disease.1,33 In this study, thromboembolic events occurred in 15.1% of such patients receiving dalteparin sodium 2500 units daily versus 9.3% of patients receiving dalteparin sodium 5000 units daily when prophylaxis was initiated the night before surgery and continued for 7 days.1,33 Despite the doubling of dosage, however, the incidence of bleeding events in patients receiving dalteparin sodium 5000 units daily was only slightly higher (but not significantly so) than that in those receiving the lower dosage.1,33

Medical Conditions Associated with Thromboembolism

Dalteparin is used for the prevention of DVT, which may lead to PE, in patients whose mobility is severely restricted during acute illness.1,125,1001

In a placebo-controlled, short-term (14 days), double-blind study in acutely ill medical patients with severely impaired mobility, therapy with subcutaneous dalteparin sodium (5000 units once daily) decreased the incidence of the primary efficacy end point at day 21 from approximately 5% in patients receiving placebo to about 2.8% in patients receiving dalteparin (relative risk reduction of 45%).1,125 The primary efficacy end point included confirmed symptomatic DVT or PE, asymptomatic proximal DVT detected by compression ultrasound, or sudden death.1,125 Patients were eligible for study entry if they had acute congestive heart failure, acute respiratory failure, infection without septic shock, acute rheumatologic disorders, or inflammatory bowel disease and required a hospital stay of at least 4 days.1,125 Patients without congestive heart failure or acute respiratory failure were required to have at least one additional risk factor for thromboembolism, including age 75 years and older, cancer, history of venous thromboembolism, obesity, varicose veins or chronic venous insufficiency, hormone replacement therapy, or myeloproliferative syndrome.1,125 There was no difference in overall mortality between the 2 groups.1,125 Major bleeding episodes occurred in 9 (0.49%) or 3 patients (0.16%) receiving dalteparin or placebo, respectively.1,125

Treatment decisions regarding the use of prophylactic anticoagulants in acutely ill hospitalized patients should include an assessment of the patient's individual risk of venous thromboembolism and risk of bleeding.1001 In general, pharmacologic thromboprophylaxis is recommended only in patients who are considered to be at high risk of venous thromboembolism because the risk-to-benefit trade-off between the reduction in venous thromboembolic events and bleeding is considered to be more favorable in such patients.1001 Factors that should be considered when choosing an appropriate anticoagulant include patient preference, compliance, ease of administration, and local cost considerations.1001 ACCP recommends the use of anticoagulant thromboprophylaxis (e.g., a low molecular weight heparin) in acutely ill, hospitalized medical patients at increased risk of thrombosis who are not actively bleeding and do not have an increased risk of bleeding.1001 Continued thromboprophylaxis is suggested for 6-21 days until full mobility is restored or hospital discharge, whichever comes first; extended prophylaxis beyond these periods generally is not recommended.1001 Risk of venous thromboembolism in critically ill patients in an intensive care unit (ICU) varies depending on their acute or chronic conditions (e.g., sepsis, congestive heart failure) and ICU-specific exposures and events (e.g., surgery, immobilization, mechanical ventilation, central venous catheters).1001 A low molecular weight heparin is suggested by ACCP as an option for pharmacologic thromboprophylaxis in critically ill patients who are not actively bleeding and do not have risk factors for bleeding.1001

Risk of venous thromboembolism is particularly high in patients with cancer.1001 Routine pharmacologic thromboprophylaxis generally is not recommended in cancer patients in the outpatient setting who have no additional risk factors for venous thromboembolism; however, ACCP suggests the use of prophylactic-dose low molecular weight heparin or low-dose heparin in cancer outpatients with solid tumors who have additional thromboembolic risk factors and are at low risk of bleeding.1001

Cardiac Surgery

Because the risk of venous thromboembolism in most patients undergoing cardiac surgery† is considered to be moderate, mechanical methods of prophylaxis (preferably with an intermittent pneumatic compression device) generally are recommended over pharmacologic prophylaxis.1002 However, ACCP states that use of a pharmacologic agent (e.g., a low molecular weight heparin) may be considered in cardiac surgery patients with a complicated postoperative course.1002

Thoracic Surgery

Pharmacologic thromboprophylaxis with a low molecular weight heparin or low-dose heparin is recommended by ACCP in patients undergoing thoracic surgery† who are at high risk of venous thromboembolism, provided risk of bleeding is low.1002

Neurosurgery

Patients undergoing craniotomy, especially for malignant disease, are considered to be at high risk of venous thromboembolism.1002 Although low molecular weight heparins have been used for the prevention of venous thromboembolism in such patients, the benefits of pharmacologic prophylaxis may be outweighed by the possible increased risk of intracranial hemorrhage.1002 ACCP suggests the use of a mechanical method of prophylaxis (preferably intermittent pneumatic compression) in craniotomy patients; for patients considered to be at very high risk for thromboembolism, such as those undergoing craniotomy for malignant disease†, a pharmacologic method (e.g., a low molecular weight heparin) may be added once adequate hemostasis has been established and the risk of bleeding decreases.1002

In patients undergoing spinal surgery†, a mechanical method of thromboprophylaxis (preferably intermittent pneumatic compression) also is suggested, with possible addition of pharmacologic prophylaxis (e.g., a low molecular weight heparin) in high-risk patients (e.g., those with malignancy or those undergoing surgery with a combined anterior-posterior approach) once adequate hemostasis is established and risk of bleeding decreases.1002

Trauma

In general, some form of thromboprophylaxis (with either a low molecular weight heparin, low-dose heparin, or a mechanical method) is suggested by ACCP in all patients with major trauma†.1002 For major trauma patients at high risk of venous thromboembolism, including those with acute spinal cord injury, traumatic brain injury, or spinal surgery for trauma†, ACCP suggests the use of both a pharmacologic and mechanical method of prophylaxis, unless contraindications exist.1002

Treatment and Secondary Prevention

Venous Thromboembolism in Patients with Cancer

Dalteparin is used for the extended (6 months' duration) treatment of symptomatic venous thromboembolism (DVT and/or PE) in patients with cancer to reduce the recurrence (secondary prevention) of venous thromboembolism.1 Warfarin generally is the preferred anticoagulant for long-term treatment of venous thromboembolism in patients without cancer; however, in patients with cancer, ACCP suggests the use of a low molecular weight heparin over warfarin because of a possible reduced response to warfarin therapy in such patients.1005 (See Treatment of Venous Thromboembolism under Uses, in Warfarin Sodium 20:12.04.08.) ACCP suggests extended anticoagulant therapy (beyond 3 months) in cancer patients with acute venous thromboembolism because of the high risk of recurrence in these patients.1005

Acute Venous Thromboembolism

The manufacturer states that dalteparin is not indicated for the acute treatment of venous thromboembolism†.1 However, low molecular weight heparins, including dalteparin†, are recommended by ACCP as an appropriate choice of anticoagulant for the initial treatment of acute proximal DVT or PE†.1005 In adults with venous thromboembolism, ACCP recommends that anticoagulant therapy be continued beyond the acute treatment period for at least 3 months, and possibly longer depending on factors such as the location of thrombi (e.g., distal versus proximal vein), presence of a risk factor (e.g., surgery, cancer), and the patient's risk of bleeding.1005 When warfarin therapy is being considered for long-term treatment of acute venous thromboembolism, the drug should be initiated concurrently with a parenteral anticoagulant (e.g., dalteparin), and such concurrent therapy should be continued for at least 5 days and until the INR is at least 2 for 24 hours or longer.1005 Anticoagulant therapy generally is not recommended in patients with isolated distal DVT† unless symptoms are severe and there is a risk for thrombus extension.1005

Analysis of pooled data from numerous comparative randomized clinical studies suggests that a low molecular weight heparin is at least as effective as heparin in the treatment of acute DVT or PE and further outpatient prevention of recurrent venous thromboembolism.87,89,1005 However, a low molecular weight heparin may offer certain advantages over heparin, such as more convenient administration and less risk of HIT.1005 ACCP generally suggests the use of a low molecular weight heparin or fondaparinux rather than heparin for the initial treatment of acute venous thromboembolism in adults.1005 Low molecular weight heparins and fondaparinux are considered to be comparable in efficacy and safety; therefore, the choice between these agents should be dictated by local considerations such as cost, availability, and familiarity of use.1005 Heparin may be preferred in patients with renal impairment.1005 In addition, ACCP states that IV heparin is preferred over subcutaneous therapies in patients with PE in whom thrombolytic therapy is being considered or if there is a concern about the adequacy of subcutaneous absorption.1005

For additional information on treatment of venous thromboembolism, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web].

Venous Thromboembolism in Pediatric Patients

Dalteparin is used for the treatment of symptomatic venous thromboembolism to reduce its recurrence in pediatric patients 1 month of age and older.1,170 Unlike in adults, most episodes of venous thromboembolism in children are secondary to an identifiable risk factor such as the presence of a central venous access device (e.g., central venous catheter or umbilical venous catheter).1013 Recommendations regarding the use of antithrombotic therapy in children generally are based on extrapolation from adult guidelines.1013 ACCP recommends a low molecular weight heparin or heparin for both the initial and ongoing treatment of venous thromboembolism in children.1013 Potential advantages of low molecular weight heparins include reduced need for monitoring, lack of drug or dietary interactions, reduced risk of HIT, and possible reduced risk of osteoporosis.1013 In children with central venous catheter-related thromboembolism, ACCP recommends that the catheter be removed if no longer functioning or required; at least 3-5 days of therapeutic anticoagulation is suggested prior to its removal.1013 If the central venous access device is required, ACCP suggests that anticoagulants be given until the catheter is removed.1013 For additional information on treatment of venous thromboembolism in neonates and children, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web]

Safety and efficacy for the treatment of symptomatic venous thromboembolism in pediatric patients were established in a single-arm, open-label clinical study in 38 pediatric patients with or without cancer and with symptomatic DVT and/or PE.1,170 Treatment with dalteparin resulted in resolution or regression of venous thromboembolism in most patients by the end of the 3-month study period.1 Initial dalteparin sodium dosages were based on age and body weight with subsequent dosage adjustments made during the initial 7 days of therapy to achieve a therapeutic anti-factor Xa concentration (0.5-1 unit/mL); patients achieved therapeutic anti-factor Xa concentrations within a mean of 2.6 days.1 At the end of the study, 62% of patients who achieved therapeutic anti-factor Xa concentrations had resolution of their venous thromboembolism, 21% of patients showed regression of venous thromboembolism, and 6% showed no chan no patients showed progression of their venous thromboembolism.1 One patient had a new venous thromboembolic event during the study while receiving treatment with dalteparin.1

Superficial Vein Thrombosis

Low molecular weight heparins also have been used for the treatment of superficial vein thrombosis (superficial thrombophlebitis)†.1005 ACCP suggests the use of prophylactic dosages of a low molecular weight heparin or fondaparinux for 45 days in patients with superficial vein thrombosis of at least 5 cm in length.1005

Renal Vein Thrombosis

A low molecular weight heparin is suggested by ACCP as a possible treatment option in selected neonates with renal vein thrombosis†; however, use of anticoagulant therapy is controversial for the treatment of renal vein thrombosis.1013

Acute Ischemic Stroke

Although therapeutic-dose anticoagulation has been used in patients with acute ischemic stroke†, there is strong evidence that such treatment is associated with worse outcomes than aspirin therapy in terms of increased mortality and rates of nonfatal major extracranial bleeding.1009 Therefore, ACCP recommends early treatment (within 48 hours) with aspirin over therapeutic anticoagulation to prevent recurrent cerebral thromboembolism in patients with acute ischemic stroke or TIA.1009 (See Uses: Thrombosis, in Aspirin 28:08.04.24.) However, heparin anticoagulants (i.e., low molecular weight heparins or heparin) may be used in prophylactic dosages for thromboprophylaxis in some patients with acute ischemic stroke; those with additional risk factors for venous thromboembolism are more likely to benefit from such prophylaxis.1009,1017 ACCP suggests that thromboprophylaxis with either a low molecular weight heparin (in prophylactic dosages), subcutaneous heparin, or intermittent pneumatic compression devices be used in patients with acute ischemic stroke† and restricted mobility.1009 Among the anticoagulant options, ACCP suggests the use of a low molecular weight heparin over heparin.1009 Prophylactic-dose heparin (heparin or a low molecular weight heparin) usually is initiated within 48 hours of the onset of stroke and is continued throughout the hospital stay until the patient regains mobility; such heparin therapy should not be given within the first 24 hours after administration of thrombolytic therapy.1009

A low molecular weight heparin is recommended as an option for the initial management of acute arterial ischemic stroke in children† until dissection and embolic causes have been excluded.1013 When dissection or cardioembolic causes have been excluded, daily aspirin therapy (in prophylactic dosages) is suggested for a minimum of 2 years; if arterial ischemic stroke is associated with dissection or a cardioembolic origin, ACCP suggests continued anticoagulant therapy (e.g., with a low molecular weight heparin).1013 In children with acute arterial ischemic stroke secondary to non-Moyamoya vasculopathy, ACCP recommends ongoing antithrombotic therapy (e.g., with a low molecular weight heparin) for 3 months.1013 Antithrombotic therapy generally is not recommended in neonates experiencing a first occurrence of arterial ischemic stroke in the absence of a cardioembolic origin; however, ACCP states that anticoagulant therapy (e.g., with a low molecular weight heparin) may be considered in neonates with a first episode of arterial ischemic stroke associated with a documented cardioembolic source.1013

Thromboembolism during Pregnancy

Low molecular weight heparins are used during pregnancy for prevention and treatment of venous thromboembolism† or for prevention and treatment of systemic embolism associated with prosthetic mechanical heart valves†.98,154,996,1012 For information on the use of low molecular weight heparins in pregnant women with prosthetic heart valves, see Uses: Thromboembolism Associated with Prosthetic Heart Valves.

ACCP states that a low molecular weight heparin (rather than heparin or warfarin) is the anticoagulant of choice for prevention and treatment of thromboembolism during pregnancy.1012 In pregnant women with an acute venous thromboembolic event, subcutaneous low molecular weight heparin is recommended for initial treatment and for secondary prevention throughout the remainder of the pregnancy.1012 ACCP suggests that anticoagulant therapy be continued for at least 6 weeks postpartum (for a minimum total duration of 3 months) to prevent recurrence of venous thromboembolism.1012

Recommendations regarding the use of anticoagulant prophylaxis during the antepartum period in pregnant women who have a history of thromboembolism† are based on the patient's risk for recurrent events.1012 In general, prophylaxis (e.g., with a low molecular weight heparin) is suggested only in those at moderate to high risk of recurrent thromboembolism (e.g., those with a single episode of unprovoked venous thromboembolism, pregnancy- or estrogen-related venous thromboembolism, history of multiple unprovoked events).1012 Postpartum thromboprophylaxis† for 6 weeks is suggested in all pregnant women with a prior venous thromboembolic event; a low molecular weight heparin (in prophylactic or intermediate dosages) or warfarin (INR 2-3) may be used for such prophylaxis.1012

The presence of hereditary thrombophilias substantially increases the risk of pregnancy-related venous thromboembolism, and a family history of venous thromboembolism further increases this risk by twofold to fourfold.1012 Homozygous genetic mutations for factor V Leiden or prothrombin G20210A are associated with the highest risks of thromboembolism in pregnant women.1012 ACCP therefore suggests antepartum prophylaxis with a low molecular weight heparin (in prophylactic or intermediate dosages) in pregnant women with homozygous genetic mutations for factor V Leiden or prothrombin G20210A who have no personal history of venous thromboembolism, but have a family history of venous thromboembolism†; continued prophylaxis with a low molecular weight heparin or warfarin is suggested for 6 weeks postpartum.1012 For pregnant women with homozygous genetic mutations for factor V Leiden or prothrombin G20210A with no individual or family history of venous thromboembolism†, clinical vigilance is suggested during the antepartum period, followed by postpartum prophylaxis with a low molecular weight heparin or warfarin.1012 Antepartum prophylaxis is not recommended in pregnant women with other types of thrombophilias who have no history of venous thromboembolism; however, postpartum prophylaxis is suggested in such women who have a family history of venous thromboembolism.1012

Anticoagulation with subcutaneous heparin or a low molecular weight heparin is used in combination with low-dose aspirin for prevention of pregnancy loss in women with antiphospholipid antibody (APLA) syndrome in whom recurrent pregnancy loss (3 or more) has occurred†.154,1012

To avoid an unwanted anticoagulant effect on the fetus during delivery, therapy with a low molecular weight heparin should be discontinued at least 24 hours prior to induction of labor or cesarean section (or expected time of neuraxial anesthesia).1012 If an at-term woman is at very high risk for recurrent venous thromboembolism (e.g., occurrence of proximal DVT or PE within the past 2 weeks), IV heparin may be initiated at this time and then discontinued 4-6 hours prior to the expected time of delivery.1012 (See Dosage and Administration: Dosage, and see Cautions: Pregnancy and Lactation, in Warfarin 20:12.04.08.) For additional information on the use of antithrombotic therapy during pregnancy, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web].

Cardioversion of Atrial Fibrillation/Flutter

Low molecular weight heparins also have been used for the prevention of stroke and systemic embolism in patients with atrial fibrillation undergoing electrical or pharmacologic cardioversion†.999,1007 Because the risk of thromboembolism appears to be greatest when atrial fibrillation has been present for more than 48 hours, recommendations for the use of anticoagulant therapy in such patients vary based on the duration of the arrhythmia.999,1007 ACCP and other experts recommend that patients with atrial fibrillation of unknown or greater than 48 hours' duration who are to undergo elective cardioversion receive therapeutic anticoagulation (e.g., usually with warfarin) for at least 3 weeks prior to cardioversion; an alternative strategy is to use a transesophageal echocardiography (TEE)-guided approach in which patients receive therapeutic anticoagulation with a low molecular weight heparin or heparin at the time of TEE and undergo cardioversion within 24 hours if no thrombus is detected.999,1007 Patients with atrial fibrillation of short duration (e.g., 48 hours or less) usually do not require prolonged anticoagulation or TEE prior to cardioversion; instead, ACCP suggests that such patients receive therapeutic anticoagulation (e.g., with a low molecular weight heparin or heparin) at presentation, followed by immediate cardioversion.1007 In patients requiring urgent cardioversion because of hemodynamic instability, initiation of a parenteral anticoagulant (e.g., IV heparin or a low molecular weight heparin) in therapeutic doses is suggested prior to cardioversion, if possible; however, initiation of the anticoagulant must not delay any emergency intervention.999,1007 After successful cardioversion to sinus rhythm, experts recommend that all patients receive therapeutic anticoagulation for at least 4 weeks.999,1007

In patients undergoing cardioversion for atrial flutter†, experts state that the same approach to thromboprophylaxis should be used as for those with atrial fibrillation.999 1007

Thromboembolism Associated with Prosthetic Heart Valves

A low molecular weight heparin or heparin is used during conversion to maintenance therapy with oral anticoagulants (e.g., warfarin) to reduce the incidence of thromboembolism (e.g., stroke) in patients with prosthetic mechanical heart valves†. 1008 In the absence of a bleeding risk, ACCP suggests bridging anticoagulation (administration of a low molecular weight heparin in either prophylactic or therapeutic dosages or heparin in prophylactic dosages) during the early postoperative period after insertion of a mechanical heart valve until an adequate response to warfarin is obtained.1008 (See Dosage and Administration: Dosage.) In patients with a mechanical heart valve in whom therapy with warfarin must be temporarily discontinued (e.g., those undergoing major surgery), bridging anticoagulation with a low molecular weight heparin or heparin also is suggested in selected patients (e.g., those at high risk of thromboembolism).1004 (See Uses: Thromboembolism Associated with Prosthetic Heart Valves, in Warfarin 20:12.04.08.)

Women with mechanical prosthetic heart valves may be at even higher risk for thromboembolism during pregnancy;112,131,132,134,139,1012 thrombosis of prosthetic heart valves, sometimes resulting in death of the mother and/or fetus, has occurred in some pregnant women receiving prophylaxis with a low molecular weight heparin (enoxaparin).108,110,111,112,113,114,129,131 Although a causal relationship has not been established and the number of patients involved appears to be small, these deaths may have been related to therapeutic failure or inadequate anticoagulation.111,115 Experts state that definitive recommendations about optimal antithrombotic therapy in pregnant women with prosthetic mechanical heart valves† currently are not possible because of a lack of properly designed studies but that fixed-dose low molecular weight heparin or low-dose, poorly controlled heparin therapy is not effective in preventing systemic embolism in such patients.98,108,111,112,113,114,128,129,130,132,133,134 Although the manufacturer of dalteparin states that the drug has not been studied systematically in patients with prosthetic heart valves,102 ACCP and other clinicians state that the use of aggressive, adjusted-dose therapy with a low molecular weight heparin (i.e., given twice daily and adjusted to maintain the manufacturer-recommended peak anti-factor Xa concentrations 4 hours postinjection) may be a reasonable approach in pregnant women with prosthetic mechanical heart valves.154,996 1012 (See Uses: Thromboembolism Associated with Prosthetic Heart Valves, in Enoxaparin 20:12.04.16.)

Cerebral Venous Sinus Thrombosis

ACCP as well as ACC, AHA, and the American Stroke Association (ASA) suggest use of a low molecular weight heparin or heparin for the treatment of acute cerebral venous sinus (sinovenous) thrombosis† in adults; such therapy should be continued until the patient is stable.1009,1017 The patient's therapy may then be converted from heparin to coumarin anticoagulant therapy.1009,1017 AHA and ASA state that it is reasonable to use a low molecular weight heparin in full doses rather than heparin for treatment of acute cerebral venous sinus thrombosis during pregnancy.1017 In addition, AHA and ASA suggest that prophylaxis with a low molecular weight heparin during pregnancy and the postpartum period is reasonable in women with a history of cerebral venous sinus thrombosis.1017

In children with cerebral venous sinus thrombosis† without substantial intracranial hemorrhage, initial anticoagulation with a low molecular weight heparin or heparin is recommended, followed by a low molecular weight heparin or warfarin for at least 3 months.1013 Another 3 months of anticoagulation is suggested if symptoms persist or there is continued occlusion of the cerebral venous sinuses.1013 Although the evidence is not as compelling as for children without substantial hemorrhage, ACCP also suggests that anticoagulation may be used for the treatment of cerebral venous sinus thrombosis in children with substantial hemorrhage.1013 Low molecular weight heparins also are suggested by ACCP as a treatment option for neonates with cerebral sinovenous thrombosis†.1013 For additional information on the use of anticoagulants in children with cerebral venous sinus thrombosis, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web].

Perioperative Antithrombotic Prophylaxis

Low molecular weight heparins are used in the perioperative management of patients who require temporary interruption of long-term warfarin therapy for surgery or other invasive procedures†.1004 Perioperative use of a low molecular weight heparin or IV heparin during the period of interruption of warfarin therapy (bridging anticoagulation†) is recommended by ACCP in some patients with venous thromboembolism, atrial fibrillation, or prosthetic mechanical heart valves depending on their risk of developing thromboembolism without warfarin therapy.1004 In general, bridging anticoagulation is suggested in such patients who are considered to be at particularly high risk of developing thromboembolism.1004 The decision to administer bridging anticoagulation should be individualized based on the patient's risk of thromboembolism versus bleeding.1004 For additional information on the perioperative management of antithrombotic therapy, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at [Web].

Administration

Dalteparin sodium is administered by deep subcutaneous injection; it must not be given IM .1 Patients should be sitting or supine during administration of the drug.1 Injections may be made into the U-shaped area around the navel, the upper outer aspect of the thigh, or the upper outer quadrangle of the buttock; injection sites should be alternated daily.1 When injecting dalteparin into the area around the navel or the thigh, the needle should be inserted into a skin fold created by the thumb and forefinger; the skin should be held until the needle is withdrawn.1 When injecting dalteparin, the entire length of the needle should be inserted at a 45-90° angle.1 The injection is commercially available in prefilled syringes equipped with a 27-gauge ½-inch needle.1

In general, dalteparin should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.1

Dosage

Dosages for dalteparin sodium or other low molecular weight heparins and for heparin cannot be used interchangeably on a unit-for-unit (or mg-for-mg) basis .1,3,5,9

Dosage of dalteparin sodium is expressed in anti-factor Xa international units (IU, units).1,2 Each mg of dalteparin sodium is equivalent to 156.25 units.1

Dosage adjustment and routine monitoring of coagulation parameters generally are not necessary if recommended regimens are followed.1,152 Monitoring of anti-factor Xa concentrations may be useful in certain high-risk patient groups, such as pregnant women with mechanical prosthetic heart valves and patients with severe renal impairment, abnormal coagulation parameters, or bleeding; anti-factor Xa concentrations should also be monitored periodically in pediatric patients receiving therapeutic dosages of low molecular weight heparins.1,152,1012,1013

If a low molecular weight heparin is used for anticoagulation in pregnant women with mechanical prosthetic heart valves, frequent monitoring of peak and trough anti-factor Xa concentrations should be used to assess anticoagulation and dosage adjusted as necessary.111,996 (See Patients with Mechanical Prosthetic Heart Valves under Warnings/Precautions: Warnings, in Cautions in Enoxaparin 20:12.04.16.) The American College of Chest Physicians (ACCP) and other clinicians recommend twice-daily dosing of low molecular weight heparins in pregnant women, at least initially, because of the altered pharmacokinetics of these drugs in such women.996,1012

The manufacturer states that when dalteparin therapy is initiated in a pediatric patient, the anti-factor Xa concentration should be measured prior to the fourth dose.1 Blood samples to measure the anti-factor Xa concentration should be drawn 4 hours after dalteparin administration.1 Anti-factor Xa concentrations are used to adjust the dosage of dalteparin sodium in order to achieve a therapeutic anti-factor Xa concentration (0.5-1 unit/mL).1 Anti-factor Xa concentrations should be monitored periodically in pediatric patients to maintain an anti-factor Xa concentration between 0.5-1 unit/mL.1 Alternatively, ACCP suggests that if a low molecular weight heparin is used for anticoagulation in children, the dosage of the drug should be adjusted to a target anti-factor Xa concentration of 0.5-1 unit/mL based on a sample taken 4-6 hours following subcutaneous administration, or 0.5-0.8 units/mL based on a sample taken 2-6 hours following subcutaneous administration.1013

In general, when warfarin is used for follow-up therapy after dalteparin, therapy with the 2 drugs is overlapped until an adequate response to warfarin is obtained, as indicated by international normalized ratio (INR) determinations.1005 (See Dosage and Administration: Dosage, in Warfarin 20:12.04.08.) ACCP recommends that dalteparin and warfarin be used concurrently for a minimum of 5 days and until the INR is at least 2 for 24 hours or longer.1005

Unstable Angina and Non-ST-Segment-Elevation Myocardial Infarction

For reducing the risk of ischemic complications in patients with unstable angina or non-ST-segment-elevation myocardial infarction (i.e., non-ST-segment-elevation acute coronary syndromes), the usual dosage of dalteparin sodium is 120 units/kg (up to a maximum of 10,000 units) every 12 hours by subcutaneous injection.1 Concurrent aspirin therapy is recommended in all patients except when contraindicated.1 Anticoagulant therapy should be administered as soon as possible after hospital admission.991 Treatment should continue until the patient is clinically stabilized, generally for 5-8 days. 1

Prevention of Deep-Vein Thrombosis and/or Pulmonary Embolism

Hip-Replacement Surgery

For the prevention of postoperative deep-vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing hip-replacement surgery, several dosing options are recommended by the manufacturer for dalteparin therapy.1,60 The drug may be initiated either before or after surgery.1 With preoperative administration, the manufacturer states that a dose of 5000 units of dalteparin sodium may be given 10-14 hours before surgery (the evening prior to the procedure), followed by a second dose of 5000 units 4-8 after surgery (or later if hemostasis has not been achieved).1 An alternative, manufacturer-recommended preoperative regimen is 2500 units given within 2 hours before surgery, followed by a second dose of 2500 units 4-8 hours after surgery (or later if hemostasis has not been achieved).1 With postoperative administration, a dose of 2500 units of dalteparin sodium may be given 4-8 hours after surgery (or later if hemostasis has not been achieved).1 ACCP states that risk of bleeding is closely associated with the timing of initiation of thromboprophylaxis around surgery.1003 Although administration times closer to surgery have been recommended by the manufacturer for the first dose of dalteparin sodium,1 ACCP recommends that low molecular weight heparins be initiated at least 12 hours preoperatively or at least 12 hours postoperatively in patients undergoing major orthopedic surgery.1003 Dalteparin sodium therapy should be continued throughout the postoperative period at a dosage of 5000 units once daily,1 generally for 5-10 days; ACCP recommends a minimum of 10-14 days of thromboprophylaxis, with extended prophylaxis suggested for up to 35 days on an outpatient basis.1003

General/Abdominal Surgery

For the prevention of postoperative DVT in patients undergoing general/abdominal surgery who are at risk for thromboembolic complications, the usual dosage of dalteparin sodium is 2500 units daily by subcutaneous injection.1,5,6,7,8,9,30 The initial dose should be given 1-2 hours before surgery,1,6,8,9,19,21 followed by daily administration of the same dosage throughout the postoperative period, generally for 5-10 days, until the risk of DVT has diminished.1,6,7,8,9,10,19,20,21

A higher dalteparin sodium dosage is recommended in patients undergoing abdominal surgery associated with a high risk of thromboembolism (e.g., surgery for malignant disease).1 In such patients, a dosage of 5000 units of dalteparin sodium once daily is recommended; the initial dose should be administered the evening prior to surgery, followed by daily administration of 5000 units throughout the postoperative period.1,30,33 Alternatively, in patients with malignancy, 2500 units of dalteparin sodium may be administered subcutaneously 1-2 hours prior to surgery, followed 12 hours later by a second dose of 2500 units, then 5000 units once daily throughout the postoperative period.1,30,33 With either dosing regimen, the manufacturer states that the usual duration of thromboprophylaxis is 5-10 days.1 Because the risk of venous thromboembolism is particularly high in patients undergoing abdominal or pelvic surgery for cancer, ACCP recommends that therapy with a low molecular weight heparin be continued for up to 4 weeks in such patients.1002

Medical Conditions Associated with Thromboembolism

For prevention of venous thromboembolism in acutely ill medical patients with severely restricted mobility, the usual dosage of dalteparin sodium is 5000 units once daily.1 The duration of prophylaxis in clinical trials was 12-14 days.1

Extended Treatment of Venous Thromboembolism in Cancer Patients

For the extended treatment of symptomatic venous thromboembolism (DVT and/or PE) in patients with cancer to reduce recurrence (secondary prevention), the manufacturer recommends an initial dalteparin sodium dosage of 200 units/kg once daily (based on total body weight) for the first 30 days of treatment, followed by a dosage of approximately 150 units/kg once daily for up to 6 months; the total daily dosage should not exceed 18,000 units.1 Safety and efficacy of treatment beyond 6 months have not been evaluated in cancer patients with acute symptomatic venous thromboembolism.1

In patients with thrombocytopenia, the daily dosage of dalteparin sodium should be reduced by 2500 units in patients with platelet counts of 50,000-100,000/mm³ until platelet counts recover to at least 100,000/mm³.1 If platelet counts decrease to 50,000/mm³ or less, therapy should be discontinued until recovery of platelet count to greater than 50,000/mm³.1

Treatment of Symptomatic Venous Thromboembolism in Pediatric Patients

For the treatment of symptomatic venous thromboembolism in pediatric patients, the initial dosage of dalteparin sodium is based on age and body weight.1 (See Table 1.)

After dalteparin has been initiated, the anti-factor Xa concentration should be measured prior to the fourth dose.1 Blood samples to measure the anti-factor Xa concentration should be drawn 4 hours after the administration of dalteparin.1 The dosage of dalteparin sodium should then be adjusted in increments of 25 units/kg to achieve a target anti-Xa concentration between 0.5-1 unit/mL.1 The maintenance dosage is the dosage that achieves the target anti-factor Xa concentration in blood collected 4 hours after administration of dalteparin.1 Anti-factor Xa concentrations should be monitored periodically in pediatric patients to maintain an anti-Xa concentration between 0.5-1 unit/mL.1

The daily dosage of dalteparin sodium should be reduced by 50% in pediatric patients (4 weeks to less than 17 years of age) with platelet counts of 50,000-100,000/mm³ until platelet count recovers to at least 100,000/mm³.1 If platelet counts in such patients decrease to 50,000/mm³ or less, therapy should be discontinued until recovery of platelet count to greater than 50,000/mm³.1

Whenever possible, preparations that do not contain benzyl alcohol (prefilled syringes) should be used in pediatric patients.1 (See Cautions: Benzyl Alcohol in Neonates and Infants and see Cautions: Pediatric Precautions.)

Treatment and Prevention of Thromboembolism During Pregnancy

For the initial treatment of acute venous thromboembolic events in pregnant women†, dalteparin sodium at a dosage of 200 units/kg daily in 1 or 2 divided doses is recommended by ACCP and should be continued throughout the remainder of the pregnancy. 1012 Anticoagulation should be continued postpartum for at least 6 weeks (minimum total duration of 3 months).1012

If dalteparin sodium is used for postpartum prophylaxis in pregnant women with a prior venous thromboembolic event†, a prophylactic (e.g., 5000 units once daily) or intermediate (e.g., 5000 units every 12 hours) dosage is suggested.1012

In pregnant women receiving long-term coumarin anticoagulation (e.g., warfarin)†, ACCP suggests the use of a low molecular weight heparin throughout pregnancy given in a weight-adjusted dosage (e.g., dalteparin sodium 100 units/kg twice daily or dalteparin sodium 200 units/kg once daily) or 75% of a weight-adjusted dosage, followed by postpartum resumption of long-term coumarin anticoagulation.1012

If dalteparin sodium is used for primary prevention of venous thromboembolism in pregnant women with certain high-risk thrombophilias†, a prophylactic (e.g., 5000 units once daily) or intermediate (e.g., 5000 units every 12 hours) dosage is suggested.1012

In women with antiphospholipid antibody (APLA) syndrome†, antepartum administration of a low molecular weight heparin in prophylactic dosages combined with low-dose aspirin (75-100 mg daily) is recommended by ACCP.1012

To avoid an unwanted anticoagulant effect on the fetus during delivery, therapy with a low molecular weight heparin should be discontinued at least 24 hours prior to induction of labor or cesarean section.1012 If an at-term woman is at very high risk for recurrent venous thromboembolism (e.g., occurrence of proximal DVT within the past 2 weeks), IV heparin may be initiated at this time and then discontinued 4-6 hours prior to the expected time of delivery.1012

Whenever possible, preservative-free preparations of dalteparin (prefilled syringes) should be used during pregnancy.1 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

Cardioversion of Atrial Fibrillation/Flutter

If dalteparin sodium is used for the prevention of stroke and systemic embolism in patients undergoing cardioversion for atrial fibrillation or atrial flutter†, administration of full-treatment dosages used for venous thromboembolism is recommended.1007

Perioperative Antithrombotic Prophylaxis

If dalteparin is used for bridging anticoagulation in patients who require temporary interruption of warfarin therapy during surgery or other invasive procedure†, ACCP recommends the use of therapeutic dosages (e.g., dalteparin sodium 100 units/kg twice daily or 200 units/kg once daily) because of more extensive data and experience; however, other dosage regimens have been used.1004

ACCP suggests that the last preoperative dose of dalteparin sodium be given approximately 24 hours prior to surgery to allow sufficient time for anticoagulant effects to dissipate.1004 Postoperative anticoagulation should be administered with caution and only when hemostasis has been achieved because of the potential for bleeding at the surgical site.1004 In patients undergoing procedures associated with a high risk of bleeding, ACCP suggests delaying the resumption of therapeutic-dose dalteparin until 48-72 hours after surgery when adequate hemostasis has been achieved.1004

Dosage in Renal and Hepatic Impairment

The manufacturer recommends caution in using dalteparin sodium in patients with severe renal or hepatic insufficiency.1 Anti-factor Xa concentrations may be monitored to determine appropriate dosage in high-risk patients, such as pregnant women, patients with severe renal impairment, patients at extremes of weight, or if abnormal coagulation parameters or bleeding occurs during therapy.1,152 Limited evidence indicates that elimination of the drug may be delayed in patients with chronic renal insufficiency requiring hemodialysis.1 ACCP suggests that dosages of low molecular weight heparins be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).1000

In adults with cancer and severe renal impairment (creatinine clearance less than 30 mL/minute) who are receiving extended treatment for acute symptomatic venous thromboembolism, the dosage of dalteparin sodium should be adjusted to a target anti-factor Xa concentration of 0.5-1.5 units/mL.1 Blood samples to measure anti-factor Xa concentration should be drawn 4-6 hours after dosing and only after the patient has received at least 3 or 4 doses.1

Dalteparin generally is well tolerated.1,6,7,8,9,10,19,20,21,33,34 Although adverse reactions to dalteparin generally are mild, discontinuance has been required in approximately 1-5% of patients receiving the drug in clinical trials, principally because of hemorrhagic complications.6,7,21,33 The incidence of minor hemorrhagic complications with dalteparin is similar to or lower than that with heparin.1,7,8,9,20,21,34 The most frequent adverse effect of dalteparin is hematoma at the injection site.1,8,9,10,19,20,21,33,34

Spinal/Epidural Hematomas

Spinal or epidural hemorrhage and subsequent hematomas can occur with concurrent use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.1,35,77,78,79 (See Cautions: Precautions and Contraindications.)

Other Hematologic Effects

The incidence of hemorrhagic complications during dalteparin therapy is low.1,6,7,19,20,21,33 The incidence of hemorrhage may increase with higher doses of the drug;1,33 however, in patients with malignancy undergoing abdominal surgery, a significant increase in hemorrhage was not observed in patients receiving dalteparin sodium 5000 units compared with those receiving dalteparin sodium 2500 units or low-dose heparin.1 In a clinical trial in patients undergoing surgery for malignancy, the incidence of hemorrhagic events was 4.6% in those receiving dalteparin sodium 5000 units once daily and 3.6% in those receiving 2500 units once daily (the difference was not significant).1 In a subgroup of patients undergoing surgery for malignancy in a similar trial, the incidence of hemorrhagic events was 3.2 or 2.7% in patients receiving dalteparin sodium 5000 units once daily or heparin sodium 5000 units twice daily, respectively.1

Major hemorrhagic events (e.g., intracranial hemorrhage, a hemoglobin decrease of at least 2 g/dL with an observed bleeding site, hemorrhage associated with death, or hemorrhage requiring a blood transfusion or drug discontinuance)1 in patients with acute coronary syndromes occurred in 1, 1, or 0.5% of patients receiving dalteparin subcutaneously, heparin IV and subcutaneously, or placebo injection subcutaneously, respectively, in controlled clinical trials.1 In several comparative clinical trials in patients undergoing hip-replacement surgery, major hemorrhagic events occurred in 2.5-3.6, 0.4-3.1, or 4.3% of patients receiving subcutaneous dalteparin, oral warfarin, or subcutaneous heparin, respectively.1 In a clinical trial in acutely ill medical patients with severely restricted mobility, major hemorrhagic events occurred in 0.49 or 0.16% of patients receiving dalteparin or placebo, respectively.1 Major hemorrhagic events in patients receiving dalteparin and undergoing hip-replacement surgery included wound hematoma (reoperation was required in at least one patient), bleeding from the operative site, intraoperative bleeding as a result of vessel damage, and GI bleeding.1

The most frequent adverse hematologic effect of dalteparin is hematoma at the injection site,1,8,9,10,19,20,21,33,34 which occurred in 0.2-7.1% of patients receiving the drug in clinical trials.1 In comparison, hematoma at the injection site was reported in 1.1-9.5% of patients receiving heparin and 1.1% of patients receiving placebo in these clinical trials.1 In patients undergoing hip-replacement surgery, hematoma at the injection site was reported in 1.1-2.9 or 10.1% of patients receiving subcutaneous dalteparin or heparin, respectively.1 Wound hematomas1,6,7,8,9,10,19,20,21,33 occurred in 0.1-3.4, 1.2-3.9, or 2.6% of patients receiving dalteparin, heparin, or placebo, respectively, in these clinical trials.1 Wound hematomas1 occurred in 2.2% of patients undergoing hip-replacement surgery receiving dalteparin, and in none of the patients receiving heparin or warfarin in these clinical trials.1

In clinical trials in patients undergoing abdominal surgery, postoperative transfusions1,6,7,8,9,10,19,20,21,33 were required in 5.7-8.7 or 12.1-15.9% of patients receiving dalteparin sodium 2500 or 5000 units once daily, respectively.1 In these trials in patients undergoing abdominal surgery, postoperative transfusions were required in 7.1 or 7.9-12.7% of patients receiving placebo or heparin sodium 5000 units twice daily, respectively.1 Reoperation because of hemorrhage1,7,9,19,33 was required in 0.5-1.3% of patients undergoing abdominal surgery receiving dalteparin in these clinical trials,1 and in 0.4-0.8 or 1.3% of patients receiving heparin or placebo, respectively.1 Postoperative hemorrhage,7,8,9,21,33 injection site bruising,6,7 perioperative hemorrhage,6,7,8,10,19,20,21,33 gastric hemorrhage,9 vaginal hemorrhage,21 and hematuria6,21 also have been reported with dalteparin in patients undergoing abdominal surgery. In clinical trials in patients undergoing hip-replacement surgery, hematuria was reported in 2.9 or 1.8% of patients receiving subcutaneous dalteparin or oral warfarin, respectively.1

Thrombocytopenia1,34 with platelet counts less than 50,000/mm³ was reported in less than 1% of adults receiving dalteparin for noncancer indications in clinical trials.1 In the clinical trial in adults with cancer receiving extended dalteparin therapy (i.e., up to 6 months) for acute symptomatic venous thromboembolism, thrombocytopenia with platelet counts less than 50,000 or less than 100,000/mm³ occurred in 6.5 or 13.6%, respectively, of patients who received the drug; dosage reduction or treatment interruption was necessary in such patients.1 Thrombocytopenia1,34 with platelet counts less than 100,000/mm³ was reported in 37% of pediatric patients (with or without cancer) receiving dalteparin for acute symptomatic venous thromboembolism in a clinical trial.1,170 Platelet counts of less than 50,000/mm³ were reported in 21% of patients in this trial; dalteparin therapy was interrupted in patients whose platelet count fell below 50,000/mm³.1 Thrombocytopenia with thrombosis, amputation, and death, also has been reported.1 (See Cautions: Precautions and Contraindications.)

Dermatologic and Sensitivity Reactions

Allergic reactions1,19,33,34 (including pruritus,1,6,11 rash,1 fever,1 injection site reactions,1,6,11,12 and bullous eruptions)1 and skin necrosis1,34 have occurred rarely in patients receiving dalteparin.1 Anaphylactoid reactions1 also have been reported in patients receiving the drug.1

Local Effects

Injection site pain1 occurred in 12% of patients undergoing hip-replacement surgery receiving dalteparin and in up to 13% of patients receiving heparin in clinical trials.1 Injection site pain1,10,19,20,33 occurred in up to 4.5% of patients undergoing abdominal surgery receiving dalteparin and in up to 11.8% of patients receiving heparin in clinical trials.1 Hematoma at the injection site also has been reported. (See Cautions: Hematologic Effects.) Hyperkalemia also has been reported with dalteparin.13

Hepatic Effects

Asymptomatic increases in serum AST (SGOT) and ALT (SGPT) concentrations1,21,34 exceeding 3 times the upper limit of normal have been reported in 1.7 and 4.3%, respectively, of patients receiving dalteparin.1 Similar increases in serum aminotransferase concentrations also have occurred in patients receiving other low molecular weight heparins or heparin.1,34 These elevations are completely reversible and rarely associated with increases in serum bilirubin concentration.1

Benzyl Alcohol in Neonates and Infants

The multiple-dose vial of dalteparin (Fragmin^®) contains 14 mg of benzyl alcohol per mL as a preservative; the prefilled syringes are preservative free.1 Benzyl alcohol has been associated with serious and fatal adverse effects in neonates and low-birth weight infants.1 (See Cautions: Pediatric Precautions.)

Precautions and Contraindications

The possibility of an underlying bleeding disorder should be ruled out before initiating dalteparin therapy.1 The usual precautions and contraindications associated with heparin anticoagulant therapy should be followed in patients for whom dalteparin therapy is considered.1 Dalteparin should be used with extreme caution in patients with an increased risk of hemorrhage.1 Factors that may increase the risk of hemorrhage during dalteparin therapy include severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic GI disease, hemorrhagic stroke, or recent brain, spinal, or ophthalmologic surgery.1

As with other anticoagulants, bleeding may occur at any site during dalteparin therapy.1 If severe hemorrhage or dalteparin overdosage occurs, protamine sulfate should be administered immediately.1 To largely neutralize the effects of dalteparin following overdosage, the dose of protamine sulfate is determined by the administered dose of the low molecular weight heparin, the time elapsed since the drug was given, and blood coagulation studies.1 The dose of protamine sulfate to be given should be equal to that of the administered dalteparin dose if dalteparin was administered in the previous 8 hours (i.e., 1 mg of protamine sulfate should be given to neutralize 100 anti-factor Xa units of dalteparin sodium).1 If more than 8 hours has elapsed since dalteparin was administered, an infusion of 0.5 mg of protamine sulfate may be given for each 100 anti-factor Xa units of dalteparin sodium administered.1 If the activated partial thromboplastin time (aPTT) measured 2-4 hours after the first protamine infusion remains prolonged, a second dose of 0.5 mg of protamine sulfate may be given for each 100 anti-factor Xa units of dalteparin sodium administered.1 Protamine administration may not be required if more than 12 hours has elapsed since administration of dalteparin.1 However, even after higher dosages of protamine sulfate, the aPTT may remain more prolonged than would be the case following treatment of overdosage of conventional heparin since anti-factor Xa activity is never completely neutralized.1 A maximum of about 60-75% of anti-factor Xa activity is neutralized with protamine sulfate administration for overdosage of dalteparin.1

Concurrent use of a low molecular weight heparin or heparinoid (e.g., danaparoid [no longer commercially available in the US]) with neuraxial (spinal/epidural) anesthesia or spinal puncture procedures has been associated with epidural or spinal hematomas.1,35,77,163 More than 15 cases of spinal/epidural hematoma associated with the concurrent use of dalteparin and neuraxial anesthesia have been reported since market introduction of the drug in 1985.1 Hematomas occurring in some of these patients have resulted in neurologic injury, including long-term or permanent paralysis.1,161 The risk of these adverse events is increased by the use of indwelling epidural catheters for administration of analgesia or the concomitant use of drugs that affect hemostasis, such as nonsteroidal anti-inflammatory agents (NSAIAs), platelet-aggregation inhibitors, or other anticoagulants.1,35,77,78 The risk also appears to be increased by a history of traumatic or repeated epidural or spinal puncture, spinal surgery, or spinal deformity.1,35

The risk of spinal bleeding applies to all anticoagulants when used in conjunction with neuraxial anesthesia or spinal puncture.161 Prior to performing a spinal or epidural procedure, healthcare professionals should determine as part of a preprocedure checklist whether a patient is receiving anticoagulants.161 In addition, clinicians should carefully consider the timing of spinal catheter placement and removal in relation to anticoagulant use, considering both the dosage and pharmacokinetic properties (e.g., elimination half-life) of the anticoagulant.1,161 Patients receiving dalteparin thromboprophylaxis prior to surgery can be assumed to have altered coagulation; to minimize the risk of bleeding, the manufacturer recommends that the first postoperative dose (2500 units) be administered 6-8 hours after surgery and that the second dose (2500 or 5000 units) be administered no sooner than 24 hours after the first dose.1

Insertion or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dalteparin is minimal.1 Although the optimal timing between the administration of dalteparin and neuraxial procedures is not known, the following guidelines are recommended.1 In patients receiving 2500 units of dalteparin sodium once daily, insertion or removal of a spinal catheter should be delayed for at least 12 hours after the dose.161 In patients receiving 5000 units of dalteparin sodium once daily, insertion or removal of a spinal catheter should be delayed for at least 15 hours after the dose.1 In patients receiving higher (treatment) dosages of dalteparin sodium (200 units/kg once daily or 120 units/kg twice daily), a delay of at least 24 hours is recommended between the dose and catheter placement/removal.1 In patients with renal impairment (creatinine clearance less than 30 mL/minute), a doubling of the recommended time delays (i.e., at least 24 hours after the prophylactic dosage and at least 48 hours after the treatment dosage) is recommended to account for possible prolonged elimination of dalteparin in such patients.1 The manufacturer suggests that while a specific recommendation cannot be made, administration of dalteparin should be delayed for at least 4 hours after catheter removal, taking into account a patient's risk of bleeding versus thrombosis in the context of the procedure and other patient risk factors.1

Patients receiving low molecular weight heparins or heparinoids in the setting of epidural or spinal anesthesia or lumbar puncture should be monitored frequently for signs and symptoms of neurologic impairment (e.g., midline back pain, numbness or weakness in lower limbs, bowel or bladder dysfunction).1,35 If spinal hematoma is suspected, urgent diagnosis and treatment is necessary; spinal cord decompression should be considered even though such treatment may not prevent or reverse neurologic sequelae.1,35,77,78 The manufacturer and some experts recommend against the concomitant use of a low molecular weight heparin and other drugs affecting hemostasis (e.g., aspirin, NSAIAs, platelet-aggregation inhibitors, other anticoagulants) in patients receiving spinal anesthesia.1 78,163 The decision to implement thromboprophylaxis with a low molecular weight heparin in the presence of an indwelling epidural catheter should be made with extreme care.79 Clinicians should fully consider the potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for thromboprophylaxis with anticoagulants.35

Thrombocytopenia of any degree occurring in patients receiving dalteparin should be monitored closely.1 Heparin-induced thrombocytopenia (HIT) also can occur with the administration of dalteparin.1 For patients with HIT with or without thrombosis, nonheparin anticoagulants such as lepirudin or argatroban are recommended; continued use of a low molecular weight heparin is contraindicated in such patients.1,1006

Because of an increased risk of bleeding, dalteparin should be used with care in patients receiving oral anticoagulants and/or platelet-aggregation inhibitors.1

Because serum aminotransferase determinations are important in the differential diagnosis of myocardial infarction (MI), liver disease, and pulmonary emboli, elevation of these enzymes during dalteparin therapy should be interpreted with caution.1

Dalteparin is contraindicated in patients with known hypersensitivity to the drug or to heparin or pork products.1 Dalteparin also is contraindicated in patients with active major bleeding or a history of HIT or HIT with thrombosis.1 In patients undergoing epidural/neuraxial anesthesia, use of dalteparin for the treatment of unstable angina or non-ST-segment elevation MI or for prolonged prophylaxis of venous thromboembolism is contraindicated.1

Pediatric Precautions

Safety and efficacy of dalteparin for the treatment of symptomatic venous thromboembolism have been established in pediatric patients 1 month of age and older.1 (See Venous Thromboembolism in Pediatric Patients under Deep-Vein Thrombosis and/or Pulmonary Embolism: Treatment and Secondary Prevention, in Uses.) The long-term effects of treatment with dalteparin in pediatric patients, including effects on growth and bone metabolism, are unknown.1

Each mL of Fragmin^® (dalteparin sodium injection) in multiple-dose vials contains 14 mg of benzyl alcohol as a preservative.1 Serious and fatal adverse reactions, including “gasping syndrome,” can occur in neonates and low-birth weight infants who receive drugs that contain the preservative benzyl alcohol.1,67,68,69,70,71,72 Toxicity has occurred from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in neonates, principally associated with the use of bacteriostatic 0.9% sodium chloride intravascular flush or endotracheal tube lavage solutions.1,67,68,69,70,71,72 However, the minimum amount of benzyl alcohol at which serious adverse effects may occur is not known.1 The American Academy of Pediatrics (AAP) states that use of preservative-containing flush solutions (i.e., with benzyl alcohol) clearly should be avoided in neonates; however, the presence of small amounts of benzyl alcohol in a commercially available injection should not proscribe its use in neonates.67 Because benzyl alcohol may cross the placenta, the manufacturer states that dalteparin preservative-free preparations should be used in pregnant women.1 When prescribing dalteparin in infants, the combined daily metabolic load of benzyl alcohol from all sources should be considered.1

Geriatric Precautions

While safety and efficacy of dalteparin in geriatric patients have not been established specifically, a large proportion of patients treated with the drug for prevention of postoperative deep-vein thrombosis (DVT) have been 65 years of age or older and dosage adjustments based on age were not made.2,6,7,9,10,20,30,33 In addition, limited evidence indicates that the pharmacokinetics of dalteparin are similar in geriatric and younger adults.5 However, geriatric patients may have decreased renal function and because patients with severe renal impairment may be at increased risk of dalteparin-induced toxicity.1 Careful attention to dosing intervals and concomitant agents (particularly antiplatelet agents) is advised, particularly in geriatric patients with low body weight (less than 45 kg) and in patients predisposed to decreased renal function.1

Mutagenicity and Carcinogenicity

Dalteparin did not exhibit any evidence of mutagenicity in vitro in the Ames test, mouse lymphoma cell forward mutation test, or human lymphocyte chromosomal aberration test, or in vivo in the mouse micronucleus test.1

Studies have not been performed to date to evaluate the carcinogenic potential of dalteparin.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies using dalteparin sodium at IV doses up to 2400 units/kg (14,160 units/m²) in pregnant rats and 4800 units/kg (40,800 units/m²) in pregnant rabbits did not reveal any evidence of impaired fertility or fetal harm.1 Dalteparin has been used in a limited number of women during the second and/or third trimester of pregnancy for the prevention and treatment of DVT without detectable placental transfer or evidence of adverse fetal effects or unusual adverse maternal effects.30,38,39,40,41,42,43,44,45,46,47,48 Data from published literature and postmarketing reports have not reported a clear association between dalteparin and adverse developmental effects.1 Although a causal relationship has not been established, valve thrombosis and maternal and fetal deaths have occurred in some pregnant women with prosthetic heart valves who were receiving thromboprophylaxis with a low molecular weight heparin (e.g., enoxaparin),101,107,108,109,110,111,112,113,114,115 and the manufacturer of dalteparin states that the drug has not been studied systematically in patients with prosthetic heart valves.102 The manufacturer states that dalteparin should be used during pregnancy only if clearly needed.1 (See Uses: Thromboembolism During Pregnancy, in Enoxaparin 20:12.04.16.)

Because benzyl alcohol may cross the placenta, the manufacturer states that dalteparin preservative-free preparations should be used in pregnant women whenever possible.1 (See Cautions: Benzyl Alcohol in Neonates and Infants and see Cautions: Pediatric Precautions.)

Fertility

Reproduction studies in male and female rats using subcutaneous dalteparin sodium doses up to 1200 units/kg (7080 units/m²) did not reveal any evidence of impaired fertility or reproductive performance.1

Lactation

Small amounts of dalteparin appear to be distributed into breast milk.5,36 The manufacturer states that the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for dalteparin and any potential adverse effects on the breast-fed child from dalteparin or from the underlying maternal condition.1 The American College of Chest Physicians (ACCP) recommends that low molecular weight heparins be continued in nursing women who are already receiving such therapy.1012

Description

Dalteparin, a depolymerized heparin prepared by nitrous acid degradation of heparin of porcine intestinal mucosa origin, is an anticoagulant.1,3,5,10,22,23,26 Dalteparin is commercially available as the sodium salt.1,22,26 The average molecular weight of dalteparin is approximately one-third to one-half that of heparin (5000 [90% of which ranges between 2000-000] versus 12,000 daltons); therefore, dalteparin is referred to as a low molecular weight heparin.1,3,5,10,22,26

At a given level of anti-factor Xa activity, dalteparin has less effect on thrombin than does heparin.1,3 The manufacturer states that, at recommended dosages, dalteparin does not substantially affect platelet aggregation, fibrinolysis, global clotting function tests (i.e., prothrombin time, thrombin time, activated partial thromboplastin time), or lipoprotein lipase.1,8,24,25,31 Compared with heparin, dalteparin has greater bioavailability (based on anti-factor Xa activity) after subcutaneous administration and a longer half-life, allowing less frequent administration.1,3,5,6,7,8,29

The molecular weight, pharmacokinetics, and in vitro and in vivo activity of dalteparin differ from those of other low molecular weight heparins or heparin; therefore, the drugs are not interchangeable on a unit-for-unit (or mg-for-mg) basis.1,3,5,9

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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