Dalteparin Sodium

Unstable Angina and Non-ST-Segment Elevation MI (NSTEMI)

Used to reduce the risk of acute cardiac ischemic events (death, MI) in patients with unstable angina or NSTEMI.1 49 51 52 53 54 66 103 104 991 Used concurrently with aspirin and/or other standard therapy (e.g., nitrates, β-adrenergic blockers, clopidogrel, platelet glycoprotein [GP] IIb/IIIa-receptor inhibitors).1 49 51 52 53 54 66 103 104 991

Initiate anticoagulant therapy as soon as possible after hospital admission.991

In patients undergoing an invasive management strategy, the American College of Cardiology (ACC), the American Heart Association (AHA), and the American College of Cardiology Foundation (ACCF) recommend use of an LMWH, heparin (referring throughout this monograph to unfractionated heparin), bivalirudin, or fondaparinux for anticoagulant therapy.991

In patients undergoing a conservative management strategy, recommended anticoagulants include an LMWH, heparin, or fondaparinux; fondaparinux is preferred in patients with an increased risk of bleeding.991

ACC/AHA/ACCF state that limited data are available for the use of dalteparin compared with enoxaparin in patients with unstable angina or NSTEMI.991

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

Prevention of postoperative DVT, which may lead to PE, in patients undergoing hip-replacement surgery.1 60 63 64 1003

LMWHs also have been used for prophylaxis of DVT and/or PE in patients undergoing total knee-replacement† and hip-fracture surgery†.1003

ACCP recommends routine thromboprophylaxis with a pharmacologic (e.g., LMWH) and/or mechanical method in all patients undergoing major orthopedic surgery because of high risk of postoperative venous thromboembolism; continue thromboprophylaxis for at least 10–14 days, and possibly for up to 35 days after surgery.1003

Several antithrombotic agents (e.g., LMWHs, fondaparinux, low-dose heparin, warfarin, aspirin) are recommended by ACCP for pharmacologic prophylaxis during major orthopedic surgery.1003 When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, safety, logistics, and compliance.1003

Thromboprophylaxis in General/Abdominal Surgery

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

ACCP recommends pharmacologic (e.g., LMWHs) and/or nonpharmacologic/mechanical (e.g., intermittent pneumatic compression) methods of thromboprophylaxis in patients undergoing general surgery, including abdominal, GI, gynecologic, and urologic surgery, according to the patient’s risk of thromboembolism and bleeding.1002 In general, pharmacologic prophylaxis 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 prophylaxis is used in patients undergoing general surgery, ACCP states that an LMWH or low-dose heparin is preferred.1002

Because risk of venous thromboembolism is particularly high in patients undergoing abdominal or pelvic surgery for cancer, extended (4 weeks) prophylaxis with an LMWH is recommended in such patients.1002

ACCP states that the recommendations for use of antithrombotic agents in general surgery patients can be applied to patients undergoing bariatric, vascular, and plastic/reconstructive surgery.1002

Medical Conditions Predisposing to Thromboembolism

Prevention of DVT, which may lead to PE, in patients with severely restricted mobility during acute illness.1 125 1001

In general, pharmacologic thromboprophylaxis recommended only in patients considered to be at high risk of venous thromboembolism.1001

ACCP recommends anticoagulant prophylaxis (e.g., LMWH) 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 suggested for 6–21 days until full mobility is restored or until hospital discharge, whichever comes first.1001

Use of LMWHs also suggested by ACCP for pharmacologic thromboprophylaxis in critically ill patients (e.g., those in an intensive care unit [ICU]) who are not actively bleeding and do not have risk factors for bleeding.1001

Risk of venous thromboembolism particularly high in patients with cancer.1001 Use of LMWH prophylaxis suggested by ACCP in cancer outpatients with solid tumors who have additional risk factors for thromboembolism provided risk of bleeding is low.1001

Thromboprophylaxis in Cardiac Surgery

Mechanical methods of prophylaxis generally recommended in patients undergoing cardiac surgery; however, ACCP states that an LMWH may be considered for thromboprophylaxis in cardiac surgery† patients with a complicated postoperative course.1002

Thromboprophylaxis in Thoracic Surgery

Pharmacologic thromboprophylaxis (e.g., LMWH) recommended by ACCP in patients undergoing thoracic surgery† who are at high risk of venous thromboembolism, provided risk of bleeding is low.1002

Thromboprophylaxis in Neurosurgery

LMWHs have been used for prevention of venous thromboembolism in patients undergoing craniotomy†; however, benefits of such prophylaxis may be outweighed by possible increased risk of intracranial hemorrhage.1002 ACCP states that LMWH prophylaxis may be considered in patients at very high risk of thromboembolism (e.g., those undergoing craniotomy for malignant disease) once adequate hemostasis established and risk of bleeding decreases.1002

Thromboprophylaxis with LMWHs also may be considered in high-risk patients undergoing spinal surgery† (e.g., those with malignancy or those undergoing surgery with a combined anterior-posterior approach) once adequate hemostasis established and risk of bleeding decreases.1002

Thromboprophylaxis in Trauma

LMWHs may be used for thromboprophylaxis in 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 use of both a pharmacologic and mechanical method of prophylaxis unless contraindications exist.1002

Extended Treatment of Acute Venous Thromboembolism in Cancer Patients

Used for extended (6 months' duration) treatment of symptomatic DVT and/or PE in patients with cancer to reduce recurrence (secondary prevention) of venous thromboembolism.1 Manufacturer states that safety and efficacy of treatment durations >6 months not established.1

Acute Venous Thromboembolism

Manufacturer states that dalteparin not indicated for the acute treatment of venous thromboembolism;†1 however, has been recommended by ACCP as an appropriate option for initial treatment of acute proximal DVT and/or PE.1005

LMWHs or fondaparinux generally preferred over heparin for initial treatment of acute venous thromboembolism; however, heparin may be preferred in patients with renal impairment.1005 IV heparin also may be preferred over LMWHs in patients with PE in whom thrombolytic therapy is being considered or if there is concern about adequate sub-Q absorption.1005

For long-term anticoagulant therapy, warfarin generally preferred in patients without cancer; however, ACCP suggests use of an LMWH in patients with cancer because of a possible reduced response to warfarin.1005

Continue anticoagulant therapy for ≥3 months and possibly longer depending on individual clinical situation.1005

Venous Thromboembolism in Pediatric Patients

An LMWH has been used for treatment and secondary prevention of venous thromboembolism in pediatric patients†; venous thromboembolism usually occurs secondary to an identifiable risk factor (e.g., presence of central venous access device in such patients).1013

Recommendations regarding use of antithrombotic therapy in children generally based on extrapolation from adult guidelines.1013

ACCP recommends an LMWH or heparin for both initial and ongoing treatment of venous thromboembolism in children.1013 Potential advantages of an LMWH over heparin include reduced need for monitoring, lack of drug or dietary interactions, reduced risk of heparin-induced thrombocytopenia (HIT), and possible reduced risk of osteoporosis.1013

In children with central venous catheter-related thromboembolism, ACCP recommends removal of catheter if no longer functioning or required; at least 3–5 days of therapeutic anticoagulation is suggested prior to removal.1013 If such catheters must remain in place, ACCP suggests anticoagulant therapy until catheter is removed.1013

Acute ST-Segment Elevation MI (STEMI)

LMWHs are used in combination with thrombolytic therapy and/or antiplatelet agents (e.g., aspirin, a P2Y12 receptor antagonist, GP IIb/IIIa-receptor inhibitor) during and after successful coronary artery reperfusion for the prevention of ischemic complications (e.g., death, reinfarction, stroke) in patients with acute STEMI†.145

Some experts state use of an LMWH also may be reasonable in patients with STEMI who are not receiving thrombolytic therapy, provided no contraindications to anticoagulation exist.145

Adjunctive use of an LMWH in patients with STEMI associated with improvement in short-term clinical outcomes (e.g., death, reinfarction, recurrent ischemia) with generally similar rates of bleeding complications compared with adjunctive heparin or placebo.145 147 148 149 150 151

LMWHs may be preferred over heparin in patients who have preserved renal function (Scr ≤2.5 mg/dL in men or ≤2 mg/dL in women).145

Also used for prevention of systemic embolism following STEMI in high-risk patients (e.g., patients with large or anterior MI, atrial fibrillation, previous embolus, documented left ventricular thrombus, cardiogenic shock).145

Not recommended in place of heparin as adjunctive therapy for patients with STEMI >75 years of age or who have renal dysfunction (Scr >2.5 mg/dL in men or >2 mg/dL in women).145

Treatment of Superficial Vein Thrombosis

LMWHs also have been used for spontaneous superficial vein thrombosis (superficial thrombophlebitis)†; ACCP suggests use of prophylactic dosages for 45 days in patients with superficial vein thrombosis of ≥5 cm in length.1005

Treatment of Renal Vein Thrombosis

Although use of anticoagulant therapy for renal vein thrombosis† (the most common cause of spontaneous venous thromboembolism in neonates) is controversial, LMWHs are suggested by ACCP as a possible treatment option.1013

Thromboprophylaxis in Acute Ischemic Stroke

Heparin anticoagulants (i.e., LMWHs or heparin) have been used for thromboprophylaxis in selected 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 thromboprophylaxis with an LMWH, sub-Q heparin, or intermittent pneumatic compression in patients with acute ischemic stroke† and restricted mobility; LMWH is preferred over heparin.1009

Prophylactic-dose heparin (heparin or an LMWH) usually initiated within 48 hours of onset of stroke and is continued throughout hospital stay until patient regains mobility; do not administer within the first 24 hours after thrombolytic therapy.1009

LMWHs also recommended by ACCP as an option for initial management of acute arterial ischemic stroke in children† until dissection and embolic causes have been excluded.1013 If arterial ischemic stroke is associated with dissection or a cardioembolic origin, continued anticoagulant therapy suggested.1013

In children with acute arterial ischemic stroke secondary to non-Moyamoya vasculopathy†, ACCP recommends ongoing antithrombotic therapy (e.g., with an LMWH) for 3 months.1013

LMWHs may be considered in neonates with a first episode of arterial ischemic stroke† associated with a documented cardioembolic source.1013

Thromboembolism During Pregnancy

Used during pregnancy for prevention and treatment of venous thromboembolism† and for prevention and treatment of systemic embolism associated with mechanical heart valves†.138 996 1012 (See Prevention and Treatment of Thromboembolism During Pregnancy under Dosage and Administration.)

Also has been used in combination with low-dose aspirin for prevention of recurrent pregnancy loss in women with antiphospholipid antibody (APLA) syndrome†.1012

LMWHs (rather than heparin or warfarin) are recommended by ACCP for prevention and treatment of thromboembolism during pregnancy.1012

In pregnant women with an acute venous thromboembolic event†, ACCP recommends an LMWH for initial treatment and secondary prevention throughout the remainder of the pregnancy.1012 To prevent recurrence, postpartum anticoagulation (for ≥6 weeks and for a total duration of ≥3 months) is suggested.1012

In general, thromboprophylaxis (e.g., with an LMWH) is suggested during the antepartum period only in pregnant women who have a history of thromboembolism† and are considered to be at moderate to high risk of recurrent events (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 suggested in all pregnant women with a prior venous thromboembolic event; an LMWH (in prophylactic or intermediate dosages) or warfarin (INR 2–3) may be used for such prophylaxis.1012

ACCP suggests antepartum and postpartum prophylaxis with an LMWH in some pregnant women with high-risk hereditary thrombophilias† (e.g., homozygous genetic mutations for factor V Leiden or prothrombin G20210A) who have not experienced a prior venous thromboembolic event, but have a family history of thromboembolism.1012

Discontinue LMWH therapy ≥24 hours prior to induction of labor or cesarean section (or expected time of neuraxial anesthesia) to avoid an unwanted anticoagulant effect on fetus.1012

Cardioversion of Atrial Fibrillation/Flutter

LMWHs have been used for prevention of stroke and systemic embolism in patients with atrial fibrillation or atrial/flutter undergoing electrical or pharmacologic cardioversion†.999 1007

As an alternative to prolonged anticoagulation (e.g., usually with warfarin) prior to cardioversion in patients with atrial fibrillation lasting >48 hours or of unknown duration, an LMWH (in therapeutic dosages) may be used at the time of transesophageal echocardiography (TEE), followed by cardioversion within 24 hours if no thrombus is detected.999 1007

In patients with atrial fibrillation of short duration (e.g., ≤48 hours), an LMWH (in therapeutic dosages) may be used at presentation, followed by immediate cardioversion.1007

In patients with hemodynamic instability who require urgent cardioversion, ACCP suggests administration of a parenteral anticoagulant (in therapeutic dosages) prior to cardioversion if possible; however, such anticoagulant therapy must not delay any emergency intervention.999 1007

After successful cardioversion to sinus rhythm, all patients should receive therapeutic anticoagulation for ≥4 weeks.999 1007

Thromboprophylaxis in Patients with Prosthetic Heart Valves

Used during conversion to maintenance therapy with warfarin to reduce the incidence of thromboembolism in patients with prosthetic mechanical heart valves†.1008

ACCP suggests bridging anticoagulation (an LMWH in either prophylactic or therapeutic dosages or IV heparin in prophylactic dosages) during the early postoperative period after insertion of a mechanical heart valve in patients without bleeding risk, until an adequate response to warfarin is obtained.1008

Also may be used for bridging anticoagulation in patients with a mechanical heart valve in whom therapy with warfarin must be temporarily discontinued (e.g., those undergoing major surgery).1004

Has been used for thromboprophylaxis in pregnant women with prosthetic mechanical heart valves†.138 1012 (See Thromboembolism During Pregnancy under Uses.)

Treatment of Cerebral Venous Sinus Thrombosis

May be used for the treatment of acute cerebral venous sinus (sinovenous) thrombosis† in adults.1009 1017 Once patient stabilized, may convert to coumarin anticoagulant therapy.138 1009 1017

Reasonable to use full-dose LMWH rather than heparin for treatment of acute cerebral venous sinus thrombosis during pregnancy.1017 Prophylaxis with an LMWH during pregnancy and the postpartum period is reasonable in women with history of cerebral venous sinus thrombosis.1017

Recommended by ACCP as an option for initial and follow-up anticoagulation in children with cerebral venous sinus thrombosis† without substantial intracranial hemorrhage.1013 Also has been suggested for use in children with substantial intracranial hemorrhage.1013

LMWHs also suggested by ACCP as a treatment option for neonates with cerebral sinovenous thrombosis†.1013

Perioperative Antithrombotic Prophylaxis

ACCP suggests use of an LMWH or IV heparin during temporary interruption of warfarin therapy (bridging anticoagulation†) in selected patients with venous thromboembolism, atrial fibrillation, or mechanical prosthetic heart valves undergoing surgery or other invasive procedures; use and type of bridging anticoagulation depend on patients' 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 venous thromboembolism without oral anticoagulant therapy.1004

Contraindications

• Active major bleeding.1

• History of HIT with or without thrombosis.1

• Known hypersensitivity to dalteparin, heparin, or pork products.1

• Use for unstable angina or NSTEMI or prolonged prophylaxis of venous thromboembolism in patients undergoing neuraxial (epidural/spinal) anesthesia.1

Warnings/Precautions

Spinal/Epidural Hematomas

Epidural or spinal hematoma reported with concurrent use of anticoagulants (e.g., LMWHs, heparinoids) and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.1 35 77 161 163 Such hematomas have resulted in neurologic injury, including long-term or permanent paralysis.1 161 (See Boxed Warning.)

Prior to performing a spinal or epidural procedure, determine whether a patient is receiving anticoagulants.161

Carefully consider the timing of spinal catheter placement and removal in relation to anticoagulant use, considering both dosage and pharmacokinetic properties (e.g., elimination half-life) of the anticoagulant.1 161

Assume that patients receiving dalteparin thromboprophylaxis prior to surgery have altered coagulation; administer first postoperative prophylactic dose (2500 units) 6–8 hours after surgery and second dose (2500 or 5000 units) no sooner than 24 hours after first dose.1

Insertion or removal of catheter is best performed when the anticoagulant effect of dalteparin is minimal (e.g., at least 12 hours after a low dosage [2500 or 5000 units once daily] or at least 24 hours after higher dosages [200 units/kg once daily or 120 units/kg twice daily]); optimal timing to achieve sufficiently low anticoagulant effect not known.1 Consider doubling these recommended time delays in patients with renal impairment.1

Consider delaying subsequent doses of dalteparin for at least 4 hours after catheter removal based on patient's risk of bleeding versus thrombosis.1 161

Frequently monitor for signs of neurologic impairment (e.g., midline back pain, numbness or weakness in lower limbs, bowel or bladder dysfunction).1 If spinal hematoma suspected, diagnose and treat immediately; consider spinal cord decompression even though it may not prevent or reverse neurologic sequelae.1

Other Warnings Related to Hemorrhage

As with other anticoagulants, bleeding may occur at any site during therapy.1 The risk of bleeding with dalteparin therapy varies with the indication and may increase with higher dosages.1

Use with extreme caution in patients with an increased risk of hemorrhage.1 Such patients include those with bacterial endocarditis; congenital or acquired bleeding disorders; active ulceration and angiodysplastic GI disease; hemorrhagic stroke; or recent brain, spinal, or ophthalmologic surgery.1 Increased risk for hemorrhage in patients with thrombocytopenia, platelet defects, those treated concomitantly with platelet-aggregation inhibitors; patients with uncontrolled arterial hypertension; and those with a history of recent GI ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage.1

Periodic CBCs, including platelet counts, and stool occult blood tests recommended.1 If abnormal coagulation parameters or bleeding should occur, may use anti-factor Xa levels to monitor anticoagulant effects of dalteparin.1

Thrombocytopenia

HIT can occur.1 Thrombocytopenia with thrombosis, amputation, and death reported.1 Closely monitor thrombocytopenia of any degree.1

Patients with Mechanical Prosthetic Heart Valves

Valve thrombosis resulting in death (including maternal and fetal deaths) and/or requiring surgical intervention reported during thromboprophylaxis with another LMWH (enoxaparin) in some patients (including pregnant women) with mechanical prosthetic heart valves.101 107 108 109 110 111 112 113 114 115 996 Women with mechanical prosthetic heart valves are at higher risk for thromboembolism during pregnancy,112 132 133 134 138 139 and the manufacturer states that dalteparin has not been studied systematically in patients with prosthetic heart valves.102 (See Prevention and Treatment of Thromboembolism during Pregnancy under Dosage and Administration.)

Specific Populations

Category B.1 Benzyl alcohol used as a preservative in multiple-dose vials of dalteparin may cross the placenta.1 67 Use caution when administering dalteparin in multiple-dose vials containing benzyl alcohol to pregnant women; use preservative-free formulations when possible.1 67

Small amounts distributed into milk in humans.1 5 36 Use caution in nursing women.1 ACCP recommends that LMWHs be continued in nursing women who are already receiving such therapy.1012

Safety and efficacy not established.1 30

Multiple-dose vials contain benzyl alcohol as a preservative.1 Administration of injections preserved with benzyl alcohol to premature infants has, in large amounts, been associated with toxicity and fatal “gasping syndrome”.1 67 68 69 70 71 72

Possible increased risk of bleeding in geriatric patients; however, no substantial differences in safety relative to younger adults reported.1 Pay careful attention to dosing intervals and concomitant agents (particularly antiplatelet agents), particularly in geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function.1

Use with caution in patients with severe renal impairment; greater drug accumulation can be expected in such patients.1

Common Adverse Effects

Hematoma at the injection site.1 8 9 10 19 20 21 33 34

Specific Drugs

Absorption

Bioavailability

Approximately 87% (absolute bioavailability).1 Greater bioavailability than heparin (based on anti-factor Xa activity).1 3 5 6 7 8 27 29

Onset

Mean peak plasma levels of anti-factor Xa activity generally attained about 4 hours after a single sub-Q injection.1

Distribution

Extent

40–60 mL/kg (based on anti-factor Xa activity).1

Small amounts distributed into milk.1 36

Elimination

Half-life

3–5 hours following sub-Q administration.1

Special Populations

Terminal half-life prolonged (to approximately 5.7 hours) in patients with chronic renal insufficiency requiring hemodialysis compared with healthy individuals.1

Similar pharmacokinetics in geriatric and younger patients.5

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.