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Dalteparin

Pronunciation

Pronunciation

(dal TE pa rin)

Index Terms

  • Dalteparin Sodium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Subcutaneous:

Fragmin: 25,000 units/mL (3.8 mL [DSC]); 95,000 units/3.8 mL (3.8 mL) [contains benzyl alcohol]

Solution, Subcutaneous [preservative free]:

Fragmin: 10,000 units/mL (1 mL); 2500 units/0.2 mL (0.2 mL); 5000 units/0.2 mL (0.2 mL); 7500 units/0.3 mL (0.3 mL); 12,500 units/0.5 mL (0.5 mL); 15,000 units/0.6 mL (0.6 mL); 18,000 units/0.72 mL (0.72 mL)

Brand Names: U.S.

  • Fragmin

Pharmacologic Category

  • Anticoagulant
  • Anticoagulant, Low Molecular Weight Heparin

Pharmacology

Low molecular weight heparin analog with a molecular weight of 4,000 to 6,000 daltons; the commercial product contains 3% to 15% heparin with a molecular weight <3,000 daltons, 65% to 78% with a molecular weight of 3,000 to 8,000 daltons and 14% to 26% with a molecular weight >8,000 daltons; while dalteparin has been shown to inhibit both factor Xa and factor IIa (thrombin), the antithrombotic effect of dalteparin is characterized by a higher ratio of antifactor Xa to antifactor IIa activity (ratio = 4)

Distribution

40 to 60 mL/kg

Excretion

Primarily renal (Howard 1997)

Onset of Action

Anti-Xa activity: Within 1 to 2 hours

Time to Peak

Serum: SubQ: Anti-Xa activity: ~4 hours

Duration of Action

>12 hours

Half-Life Elimination

Route dependent: Anti-Xa activity:

IV: 2.1 ± 0.3 (40 unit/kg/dose) to 2.3 ± 0.4 (60 unit/kg/dose); prolonged in chronic renal impairment requiring hemodialysis

SubQ: 3 to 5 hours

Protein Binding

Low affinity for plasma proteins (Howard 1997)

Special Populations: Renal Function Impairment

Mean terminal half-life of anti-Factor Xa activity was prolonged to 5.7 hours ± 2 hours following IV administration to patients with chronic renal impairment requiring hemodialysis.

Use: Labeled Indications

Deep vein thrombosis prophylaxis: Prevention of deep vein thrombosis (DVT) which may lead to pulmonary embolism (PE), in patients requiring abdominal surgery who are at risk for thromboembolism complications (eg, >40 years of age, obesity, patients with malignancy, history of DVT or PE, and surgical procedures requiring general anesthesia and lasting >30 minutes); patients undergoing hip-replacement surgery; or in patients who are at risk for thromboembolism complications due to severe immobility during an acute illness.

Unstable angina/non-Q-wave myocardial infarction: Prevention of ischemic complications in patients with unstable angina or non-Q-wave myocardial infarction on concurrent aspirin therapy.

Venous thromboembolism, extended treatment in cancer patients: Extended treatment (6 months) of acute symptomatic venous thromboembolism (DVT and/or PE) to reduce the recurrence of venous thromboembolism in cancer patients.

Canadian labeling: Additional use (off-label use in US): Treatment of acute DVT; prevention of venous thromboembolism (VTE) in patients at risk of VTE undergoing general surgery; anticoagulant in extracorporeal circuit during hemodialysis and hemofiltration

Use: Unlabeled

Active treatment of deep vein thrombosis (noncancer patients)

Contraindications

Hypersensitivity to dalteparin (eg, pruritus, rash, anaphylactic reactions), heparin, pork products, or any component of the formulation; history of heparin-induced thrombocytopenia (HIT) or HIT with thrombosis; active major bleeding; patients with unstable angina, non-Q-wave MI, or prolonged venous thromboembolism prophylaxis undergoing epidural/neuraxial anesthesia.

Note: Use of dalteparin in patients with current HIT or HIT with thrombosis is not recommended and considered contraindicated due to high cross-reactivity to heparin-platelet factor-4 antibody (Guyatt [ACCP], 2012; Warkentin 1999).

Canadian labeling: Additional contraindications (not in US labeling): Septic endocarditis, major blood clotting disorders; acute gastroduodenal ulcer; cerebral hemorrhage; severe uncontrolled hypertension; diabetic or hemorrhagic retinopathy; other diseases that increase risk of hemorrhage; injuries to and operations on the CNS, eyes, and ears

Dosing: Adult

Note: Each 2,500 units of anti-Xa activity is equal to dalteparin 16 mg.

Anticoagulant for hemodialysis and hemofiltration: IV: Canadian labeling (not in US labeling):

Chronic renal failure with no other bleeding risks:

Hemodialysis/filtration ≤4 hours: IV bolus: 5,000 units

Hemodialysis/filtration >4 hours: IV bolus: 30 to 40 units/kg, followed by an infusion of 10 to 15 units/kg/hour (typically produces plasma concentrations of 0.5 to 1 units anti-Xa/mL)

Acute renal failure and high bleeding risk: IV bolus: 5 to 10 units/kg, followed by an infusion of 4 to 5 units/kg/hour (typically produces plasma concentrations of 0.2 to 0.4 units anti-Xa/mL)

DVT prophylaxis: Note: In morbidly obese patients (BMI ≥40 kg/m2), increasing the prophylactic dose by 30% may be appropriate (Nutescu 2009):

Abdominal surgery:

Low-to-moderate DVT risk: SubQ: 2,500 units 1 to 2 hours prior to surgery, then 2,500 units once daily for 5 to 10 days postoperatively.

High DVT risk: SubQ: 5,000 units the evening prior to surgery and then 5,000 units once daily for 5 to 10 days postoperatively. Alternatively in patients with malignancy: 2,500 units 1 to 2 hours prior to surgery, 2,500 units 12 hours later, then 5,000 units once daily for 5 to 10 days postoperatively.

General surgery with risk factors for VTE: Canadian labeling (not in US labeling): SubQ: 2,500 units 1 to 2 hours preoperatively followed by 2,500 to 5,000 units every morning (may administer 2,500 units no sooner than 4 hours after surgery and 8 hours after previous dose provided hemostasis has been achieved) or if other risk factors are present (eg, malignancy, heart failure), then may administer 5,000 units the evening prior to surgery followed by 5,000 units every evening postoperatively; continue treatment until patient is mobilized (approximately ≥5 to 7 days)

Total hip replacement surgery: SubQ: Note: Three treatment options are currently available. Dose is usually given for 5 to 10 days, although up to 14 days of treatment have been tolerated in clinical trials. The American College of Chest Physicians (ACCP) recommends a minimum duration of at least 10 to 14 days; extended duration of up to 35 days is suggested (Guyatt 2012).

Postoperative regimen:

Initial: 2,500 units 4 to 8 hours after surgery (or later if hemostasis not achieved). The ACCP recommends initiation ≥12 hours after surgery if postoperative regimen chosen (Guyatt 2012).

Maintenance: 5,000 units once daily; allow at least 6 hours to elapse after initial postsurgical dose (adjust administration time accordingly).

Preoperative regimen (starting day of surgery):

Initial: 2,500 units within 2 hours before surgery. The ACCP recommends initiation ≥12 hours before surgery if preoperative regimen chosen (Guyatt 2012). At 4 to 8 hours after surgery (or later if hemostasis not achieved), administer 2,500 units.

Maintenance: 5,000 units once daily; allow at least 6 hours to elapse after initial postsurgical dose (adjust administration time accordingly).

Preoperative regimen (starting evening prior to surgery):

Initial: 5,000 units 10 to 14 hours before surgery. The ACCP recommends initiation ≥12 hours before surgery if preoperative regimen chosen (Guyatt 2012). At 4 to 8 hours after surgery (or later if hemostasis not achieved), administer 5,000 units.

Maintenance: 5,000 units once daily, allowing 24 hours between doses.

Immobility during acute illness: SubQ: 5,000 units once daily; in clinical trials, the usual duration of therapy was 12 to 14 days.

Unstable angina or non-Q-wave myocardial infarction: SubQ: 120 units/kg (maximum dose: 10,000 units) every 12 hours with concurrent aspirin therapy. Discontinue dalteparin once patient is clinically stable; usual duration of therapy is 5 to 8 days.

Obesity: Use actual body weight to calculate dose; dose capping at 10,000 units recommended (Nutescu, 2009)

Venous thromboembolism, extended treatment in cancer patients: SubQ:

Initial (month 1): 200 units/kg (maximum dose: 18,000 units) once daily for 30 days.

Maintenance (months 2 to 6): ~150 units/kg (maximum dose: 18,000 units) once daily. If platelet count between 50,000 to 100,000/mm3, reduce dose by 2,500 units until platelet count recovers to ≥100,000/mm3. If platelet count <50,000/mm3, discontinue dalteparin until platelet count recover to >50,000/mm3.

Obesity: Use actual body weight to calculate dose; dose capping is not recommended (Nutescu 2009). However, the manufacturer recommends a maximum dose of 18,000 units per day for the treatment of VTE in cancer patients.

Acute pulmonary embolism (noncancer-related) (off-label use): SubQ: 120 units/kg twice daily (Meyer 1995) or 200 units/kg once daily (Kovacs 2000). Note: Start warfarin on the first treatment day and continue dalteparin until INR is ≥2 for at least 24 hours (usually 5 to 7 days) (ACCP [Guyatt 2012]).

DVT (with or without PE; noncancer-related) treatment (off-label use in US): SubQ: 200 units/kg once daily (AHA [Jaff 2011]; Feissinger 1996; Wells 2005) or 100 units/kg twice daily (AHA [Jaff 2011]). Note: Use of once daily dalteparin dosing regimen is suggested. Start warfarin on the first treatment day and continue dalteparin until INR is ≥2 for at least 24 hours (usually 5 to 7 days) (ACCP [Guyatt 2012]).

Canadian labeling: SubQ: 200 units/kg once daily (maximum dose: 18,000 units/day) or alternatively, may adapt dose as follows (SubQ):

46 to 56 kg: 10,000 units once daily

57 to 68 kg: 12,500 units once daily

69 to 82 kg: 15,000 units once daily

≥83 kg: 18,000 units once daily

Note: If increased bleeding risk, may give 100 units/kg SubQ twice daily. Concomitant treatment with a vitamin-K antagonist is usually initiated immediately.

Obesity: Use actual body weight to calculate dose; dose capping is not recommended (Nutescu 2009). One study demonstrated similar anti-Xa levels after 3 days of therapy in obese patients (>40% above IBW; range: 82 to 190 kg) compared to those ≤20% above IBW or between 20% to 40% above IBW (Wilson 2001).

Pregnant women (off-label use): 200 units/kg/dose once daily or 100 units/kg/dose every 12 hours. Discontinue ≥24 hours prior to the induction of labor or cesarean section. Dalteparin therapy may be substituted with heparin near term. Continue anticoagulation therapy for ≥6 weeks postpartum (minimum duration of therapy: 3 months). LMWH or heparin therapy is preferred over warfarin during pregnancy (Bates 2012).

Mechanical heart valve (aortic or mitral position) to bridge anticoagulation (off-label use): SubQ: 100 units/kg/dose every 12 hours (ACCP [Douketis, 2012]). Note: If used in pregnant patients, target anti-Xa level of 0.8 to 1.2 units/mL, 4 to 6 hours postdose (AHA/ACC [Nishimura 2014]).

Prevention of recurrent venous thromboembolism in pregnancy (off-label use): SubQ: 5,000 units once daily. Therapy should continue for 6 weeks postpartum in high-risk women (Bates 2012).

Conversion:

Conversion from IV unfractionated heparin (UFH) infusion to SubQ dalteparin (Nutescu 2007): Calculate specific dose for dalteparin based on indication, discontinue UFH and begin dalteparin within 1 hour

Conversion from SubQ dalteparin (therapeutically dosed) to IV UFH infusion (Nutescu 2007): Note: The following recommendations are based on use of therapeutic doses of dalteparin (eg, 100 units/kg twice daily).If converting from a prophylactic dalteparin dose (eg, 5,000 units once daily) to a therapeutic IV UFH dose, there should not be any delay in starting the IV UFH infusion and may include an UFH bolus/loading dose, when indicated.

Discontinue dalteparin, calculate specific dose for IV UFH infusion based on indication, omit UFH bolus/loading dose

Converting from SubQ dalteparin dosed every 12 hours: Start IV UFH infusion 10 to 11 hours after last dose of dalteparin

Converting from SubQ dalteparin dosed every 24 hours: Start IV UFH infusion 22 to 23 hours after last dose of dalteparin

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling. Use with caution in severe renal impairment; accumulation may occur with repeated dosing, increasing the risk for bleeding. Accumulation was not observed in critically ill patients with severe renal insufficiency (CrCl <30 mL/minute) receiving prophylactic doses (5,000 units/day) for a median of 7 days (Douketis, 2008). In cancer patients, receiving treatment for venous thromboembolism, if CrCl <30 mL/minute, manufacturer recommends monitoring anti-Xa levels to determine appropriate dose.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling. Use with caution in patients with severe hepatic impairment; accumulation may occur with repeated dosing, increasing the risk for bleeding.

Dosing: Obesity

Refer to indication-specific dosing for obesity-related information (may not be available for all indications).

Reconstitution

If necessary, may dilute in isotonic sodium chloride or dextrose solutions to a concentration of 20 units/mL. Use within 24 hours of mixing (Fragmin Canadian product labeling).

Administration

For deep SubQ injection; do not administer IM. May inject in a U-shape to the area surrounding the navel, the upper outer side of the thigh, or the upper outer quadrangle of the buttock. Use thumb and forefinger to lift up a fold of skin when injecting in the navel area or thigh. Insert entire needle length at a 45- to 90-degree angle. Do not expel air bubble from prefilled syringe prior to injection. Air bubble (and extra solution, if applicable) may be expelled from graduated syringes. In order to minimize bruising, do not rub injection site. Rotate injection sites daily.

To convert from IV unfractionated heparin (UFH) infusion to SubQ dalteparin (Nutescu 2007): Calculate specific dose for dalteparin based on indication, discontinue UFH and begin dalteparin within 1 hour

To convert from SubQ dalteparin to IV UFH infusion (Nutescu 2007): Discontinue dalteparin; calculate specific dose for IV UFH infusion based on indication; omit heparin bolus/loading dose

Converting from SubQ dalteparin dosed every 12 hours: Start IV UFH infusion 10 to 11 hours after last dose of dalteparin

Converting from SubQ dalteparin dosed every 24 hours: Start IV UFH infusion 22 to 23 hours after last dose of dalteparin

IV (Canadian labeling; not an approved route in US labeling): Administer as bolus IV injection or as continuous infusion. Recommended concentration for infusion: 20 units/mL.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Multidose vials may be stored for up to 2 weeks at room temperature after entering.

Drug Interactions

5-ASA Derivatives: May enhance the adverse/toxic effect of Heparin (Low Molecular Weight). Specifically, the risk for bleeding/bruising may be increased. Monitor therapy

ACE Inhibitors: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Aliskiren: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Aliskiren. Monitor therapy

Angiotensin II Receptor Blockers: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Antithrombin: May enhance the anticoagulant effect of Heparin (Low Molecular Weight). Monitor therapy

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Canagliflozin: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Canagliflozin. Monitor therapy

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Avoid combination

Eplerenone: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Eplerenone. Monitor therapy

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Monitor therapy

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Consider therapy modification

Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Palifermin: Heparin (Low Molecular Weight) may increase the serum concentration of Palifermin. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Pentoxifylline: May enhance the anticoagulant effect of Heparin (Low Molecular Weight). Monitor therapy

Potassium Salts: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Potassium Salts. Monitor therapy

Potassium-Sparing Diuretics: Heparin (Low Molecular Weight) may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Management: Monitor serum potassium concentrations closely. The spironolactone Canadian product monograph lists its combination with heparin or low molecular weight heparins as contraindicated. Monitor therapy

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

Adverse Reactions

Note: As with all anticoagulants, bleeding is the major adverse effect of dalteparin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables.

>10%: Hematologic & oncologic: Hemorrhage (3% to 14%), thrombocytopenia (including heparin-induced thrombocytopenia, <1%; cancer clinical trials: ~11%)

1% to 10%:

Hematologic & oncologic: Major hemorrhage (≤6%), wound hematoma (3%)

Hepatic: Increased serum ALT (>3 x ULN: 4% to 10%), increased serum AST (>3 x ULN: 5% to 9%)

Local: Pain at injection site (≤12%), hematoma at injection site (≤7%)

<1% (Limited to important or life-threatening): Alopecia, anaphylactoid reaction, gastrointestinal hemorrhage, hemoptysis, hypersensitivity reaction (fever, pruritus, rash, injections site reaction, bullous eruption), postoperative wound bleeding, skin necrosis, subdural hematoma, thrombosis (associated with heparin-induced thrombocytopenia). Spinal or epidural hematomas can occur following neuraxial anesthesia or spinal puncture, resulting in paralysis.

ALERT: U.S. Boxed Warning

Spinal/Epidural hematoma:

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWHs) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; or a history of spinal deformity or spinal injury. Optimal timing between the administration of dalteparin and neuraxial procedures is not known.

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: Bleeding may occur at any site during therapy. Monitor patient closely for signs or symptoms of bleeding. Risk factors for bleeding include patients with bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplastic GI diseases; severe uncontrolled hypertension; hemorrhagic stroke; or use shortly after brain, spinal, or ophthalmology surgery; in patients treated concomitantly with other drugs known to cause bleeding (eg, platelet inhibitors); recent GI bleeding; thrombocytopenia or platelet defects; hypertensive or diabetic retinopathy; or in patients undergoing invasive procedures. Discontinue if bleeding occurs; use is contraindicated with active major bleeding. Protamine may be considered as a partial reversal agent in overdose situations (consult Protamine monograph for dosing recommendations).

• Hyperkalemia: Monitor for hyperkalemia. Heparin can cause hyperkalemia by affecting aldosterone; similar reactions could occur with LMWHs.

• Thrombocytopenia: Thrombocytopenia with thrombosis, amputation, and death have been observed; HIT may occur. Use is contraindicated in patients with a history of HIT or HIT with thrombosis. Interrupt or discontinue therapy in patients with platelet counts <100,000/mm3 and/or thrombosis related to initiation of dalteparin especially when associated with a positive in vitro test for antiplatelet antibodies. Use caution in patients with thrombocytopenia or platelet defects.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with severe hepatic impairment; accumulation may occur with repeated dosing increasing the risk for bleeding.

• Renal impairment: Use with caution in patients with severe renal impairment; accumulation may occur with repeated dosing increasing the risk for bleeding.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Obesity: There is no consensus for adjusting/correcting the weight-based dosage of LMWH for patients who are morbidly obese (BMI ≥40 kg/m2). Monitoring of anti-Xa levels 4 hours after the dose may be warranted. The American College of Chest Physicians Practice Guidelines suggest consulting with a pharmacist regarding dosing in bariatric surgery patients and other obese patients who may require higher doses of LMWH (Gould, 2012).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and should not be used in pregnant women. In neonates, large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”); the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

Other warnings/precautions:

• Conversion to other products: Not to be used interchangeably (unit for unit) with heparin or any other low molecular weight heparins.

• Neuraxial anesthesia: [US Boxed Warning]: Epidural or spinal hematomas, including subsequent long term or permanent paralysis, may occur in patients anticoagulated with LMWH or heparinoids who are receiving neuraxial anesthesia (epidural or spinal anesthesia) or undergoing spinal puncture. Consider risk versus benefit prior to spinal procedures; risk is increased by the use of concomitant agents which may alter hemostasis, the use of indwelling epidural catheters, a history of spinal deformity or spinal surgery, or a history of traumatic or repeated epidural or spinal punctures. Optimal timing between neuraxial procedures and dalteparin administration is not known. Delay placement or removal of catheter for at least 12 hours after administration of 2,500 units once daily, at least 15 hours after the administration of 5,000 units once daily, and at least 24 hours after the administration of higher doses (200 units/kg once daily, 120 units/kg twice daily) and consider doubling these times in patients with creatinine clearance <30 mL/minute; risk of neuraxial hematoma may still exist since antifactor Xa levels are still detectable at these time points. Upon removal of catheter, consider delaying next dose of dalteparin for at least 4 hours. Frequently monitor patients for signs and symptoms of neurological impairment (eg, midline back pain, sensory and motor deficits, bowel and/or bladder dysfunction) following anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture. If neurological compromise is noted, urgent treatment is necessary. If spinal hematoma is suspected, diagnose and treat immediately; spinal cord decompression may be considered although it may not prevent or reverse neurological sequelae. Use is contraindicated in patients with unstable angina and non-Q-wave MI, or for prolonged venous thromboembolism prophylaxis in patients who will be undergoing epidural/neuraxial anesthesia.

Monitoring Parameters

Periodic CBC including platelet count; stool occult blood tests; monitoring of PT and PTT is not necessary. Once patient has received 3 to 4 doses, anti-Xa levels, drawn 4 to 6 hours after dalteparin administration, may be used to monitor effect in patients with severe renal impairment or if abnormal coagulation parameters or bleeding should occur. For patients >190 kg, if anti-Xa monitoring is available, adjusting dose based on anti-Xa levels is recommended; if anti-Xa monitoring is unavailable, reduce dose if bleeding occurs (Nutescu 2009).

Signs and symptoms of neurological impairment (eg, midline back pain, sensory/motor deficits, bowel and/or bladder dysfunction).

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse effects have not been observed in animal reproduction studies. Low molecular weight heparin (LMWH) does not cross the placenta; increased risks of fetal bleeding or teratogenic effects have not been reported (Bates 2012).

LMWH is recommended over unfractionated heparin for the treatment of acute venous thromboembolism (VTE) in pregnant women. LMWH is also recommended over unfractionated heparin for VTE prophylaxis in pregnant women with certain risk factors. LMWH should be discontinued at least 24 hours prior to induction of labor or a planned cesarean delivery. For women undergoing cesarean section and who have additional risk factors for developing VTE, the prophylactic use of LMWH may be considered. For women who require long-term anticoagulation with warfarin and who are considering pregnancy, LMWH substitution should be done prior to conception when possible. When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, VTE, hemorrhage), burden of therapy, and maternal preference should be considered (Guyatt 2012). LMWH may also be used in women with mechanical heart valves (consult current guidelines for details) (Bates 2012; Nishimura 2014).

Multiple-dose vials contain benzyl alcohol (avoid in pregnant women due to association with gasping syndrome in premature infants); use of preservative-free formulation is recommended.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience injection site irritation. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of nerve problems (sensitivity to heat or cold; decreased sense of touch; burning, numbness, or tingling; pain, or weakness in the arms, hands, legs, or feet), severe dizziness, passing out, confusion, severe headache, burning or numbness feeling, or muscle weakness (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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