Dalteparin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Subcutaneous:

Fragmin: 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)

Pharmacology

Mechanism of Action

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 anti-Factor Xa to anti-Factor IIa activity (ratio = 4)

Pharmacokinetics/Pharmacodynamics

Distribution

V_d:

Pediatric:

3 to <8 weeks: 181 ± 15.3 mL/kg.

≥8 weeks to <2 years: 175 ± 55.3 mL/kg.

≥2 years to <8 years: 160 ± 25.6 mL/kg.

≥8 years to <12 years: 165 ± 27.3 mL/kg.

≥12 years to <20 years: 171 ± 38.8 mL/kg.

Adult: 40 to 60 mL/kg.

Excretion

Primarily renal (Howard 1997).

Clearance: In pediatric subjects, age-dependent changes were observed.

3 to <8 weeks: 55.8 ± 3.91 mL/hour/kg.

≥8 weeks to <2 years: 40.4 ± 8.49 mL/hour/kg.

≥2 years to <8 years: 26.7 ± 4.75 mL/hour/kg.

≥8 years to <12 years: 22.4 ± 3.41 mL/hour/kg.

≥12 years to <20 years: 18.8 ± 3.02 mL/hour/kg.

Onset of Action

Anti-Factor Xa activity: Within 1 to 2 hours.

Time to Peak

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

Duration of Action

>12 hours.

Half-Life Elimination

Route dependent:

IV: Mean terminal half-life: 2.1 ± 0.3 hours (40 unit/kg/dose) to 2.3 ± 0.4 hours (60 unit/kg/dose); mean terminal half-life (anti-Factor Xa activity): 5.7 ± 2.0 hours (5,000 unit dose in chronic renal impairment requiring hemodialysis).

SubQ:

Pediatric: Age-dependent changes were observed.

3 to <8 weeks: 2.25 ± 0.173 hours.

≥8 weeks to <2 years: 3.02 ± 0.688 hours.

≥2 years to <8 years: 4.27 ± 1.05 hours.

≥8 years to <12 years: 5.11 ± 0.509 hours.

≥12 years to <20 years: 6.28 ± 0.937 hours.

Adult: Mean terminal half-life: 3 to 5 hours.

Protein Binding

Low affinity for plasma proteins (Howard 1997).

Use in Specific Populations

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 adult patients with chronic renal impairment requiring hemodialysis.

Special Populations: Children

Clearance was observed to decrease with increasing age during infancy and early childhood. Although V_dss in pediatric patients is larger than adult patients, this difference was not observed to be affected by age.

Use: Labeled Indications

Anticoagulant for hemodialysis and hemofiltration (Fragmin [Canadian product only]): Prevention of clotting in the extracorporeal system during hemodialysis and hemofiltration in connection with acute renal failure or chronic renal insufficiency

Non-ST elevation acute coronary syndromes: Prevention of ischemic complications in patients with unstable angina or non-Q-wave myocardial infarction on concurrent aspirin therapy.

Venous thromboembolism prophylaxis: Prevention of DVT which may lead to PE, in patients requiring abdominal surgery who are at risk for thromboembolism complications (eg, >40 years, obesity, malignancy, history of DVT or PE, surgical procedures requiring general anesthesia lasting >30 minutes); patients undergoing total hip arthroplasty; or in patients who are at risk for thromboembolism complications due to severe immobility during an acute illness.

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

Venous thromboembolism treatment in pediatric patients: Treatment of symptomatic VTE (ie, DVT and/or PE) to reduce the recurrence of VTE in infants ≥1 month of age, children, and adolescents.

Use: Off Label

Acute symptomatic superficial vein thrombosis (lower extremity; ≥5 cm in length)ayes

Data from a randomized, double-blind, placebo-controlled trial support the use of dalteparin in the treatment of this condition Rathbun 2012.

Based on the American College of Chest Physicians (ACCP) guidelines on antithrombotic therapy for venous thromboembolism (VTE) disease, dalteparin is effective and recommended for use in patients with acute symptomatic superficial vein thrombosis (≥5 cm in length) of the legs.

Deep vein thrombosis and/or pulmonary embolism treatmentbyes

Data from a randomized, open label study comparing dalteparin to continuous IV infusion unfractionated heparin for the initial treatment of acute deep vein thrombosis (DVT) support the use of dalteparin Fiessinger 1996. Data from a prospective cohort study using dalteparin as a bridge to therapeutic oral anticoagulation suggest that dalteparin may be feasible and safe for the outpatient treatment of pulmonary embolism (PE) Kovacs 2000. Another clinical trial comparing the use of dalteparin to tinzaparin in patients without cancer with either DVT or PE supports the use of dalteparin for the outpatient treatment of DVT or PE as a bridge to therapeutic oral anticoagulation Wells 2005.

Based on the 2016 ACCP guidelines for antithrombotic therapy for VTE disease, low-molecular-weight-heparin (LMWH) (eg, dalteparin) is an effective and recommended treatment option for acute DVT and/or PE. However, in patients with VTE (ie, DVT or PE) without cancer, oral anticoagulants are preferred over low-molecular-weight heparin (LMWH) (unless LMWH is used as initial parenteral anticoagulation prior to dabigatran, edoxaban, or while initiating warfarin).

Mechanical heart valve (bridging anticoagulation)yes

Based on the 2017 American Heart Association/American College of Cardiology (AHA/ACC) focused update of the 2014 guideline for the management of patients with valvular heart disease, a LMWH (eg, dalteparin) is reasonable to decrease the risk of thrombotic events in patients who require temporary interruption of oral anticoagulation and have a mechanical mitral heart valve, mechanical aortic heart valve plus additional risk factors for thromboembolism (eg, atrial fibrillation, previous thromboembolism, left ventricular dysfunction, hypercoagulable condition), older-generation mechanical valves (ball-cage or tilting disc) or in pregnant patients with a mechanical prosthetic heart valve only if anti-Factor Xa levels can be monitored.

Venous thromboembolism prophylaxis, nonorthopedic surgeryyes

Based on the 2012 ACCP guideline for prevention of venous thromboembolism in nonorthopedic surgical patients, LMWH (eg, dalteparin) is an effective and recommended option for pharmacologic prophylaxis to decrease the perioperative risk of thrombotic events.

Venous thromboembolism prophylaxis, pregnancyyes

Based on the 2012 ACCP guidelines for the management of antithrombotic therapy and the 2018 American College of Obstetricians and Gynecologists clinical practice guideline on thromboembolism in pregnancy, LMWH (eg, dalteparin) is an effective and recommended option for pharmacologic prophylaxis to decrease the risk of thrombotic events.

Venous thromboembolism prophylaxis, total knee arthroplastyyes

Based on the 2012 ACCP guidelines for prevention of VTE in orthopedic surgery patients, a LMWH (eg, dalteparin) is effective and recommended for the prevention of VTE.

Venous thromboembolism treatment in pregnancyyes

Based on the 2012 ACCP guidelines for the management of antithrombotic therapy a LMWH (eg, dalteparin) is effective and recommended for the treatment of VTE during pregnancy.

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 (ACCP [Guyatt 2012]; Warkentin 1999).

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to LMWHs; history of confirmed or suspected HIT and/or patients in whom an in vitro platelet-aggregation test in the presence of dalteparin is positive; septic endocarditis (endocarditis lenta, acute or subacute endocarditis); major blood clotting disorders; acute gastroduodenal ulcer; cerebral hemorrhage; severe uncontrolled hypertension; diabetic or hemorrhagic retinopathy; other conditions or diseases that increase risk of hemorrhage; injuries to and operations on the CNS, eyes, and ears

Dosage and Administration

Dosing: Adult

Acute symptomatic superficial vein thrombosis (lower extremity; ≥5 cm in length) (off-label use): SubQ: 5,000 units every 12 hours for 45 days (ACCP [Kearon 2012]; Rathbun 2012). Risk of recurrence is high if anticoagulation is discontinued earlier than 45 days. Monitor d-dimer at baseline and again at 45 days; if d-dimer remains elevated, a longer course may be necessary (Scovell 2018).

Anticoagulant for hemodialysis and hemofiltration (off-label use): IV: (Fragmin Canadian product labeling):

Chronic renal failure with no other bleeding risks:

Hemodialysis/filtration ≤4 hours:

IV bolus: 5,000 units; may adjust dose during subsequent dialysis sessions in increments of 500 to 1,000 anti-Factor Xa units based on the outcome of the previous dialysis session. Alternatively, may administer an IV bolus of 30 to 40 units/kg, followed by an infusion of 10 to 15 units/kg/hour. Note: Both regimens typically produce plasma concentrations of 0.5 to 1 units anti-Factor Xa/mL.

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-Factor 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-Factor Xa/mL).

Mechanical heart valve (bridging anticoagulation) (off-label use): Note: Bridging during intervals of subtherapeutic anticoagulation should be considered for patients with mechanical mitral or tricuspid valve replacement; however, for patients with mechanical aortic valve replacement, bridging is not required unless an additional thromboembolic risk factor is present or patient has an older generation mechanical aortic valve (AHA/ACC [Nishimura 2017]).

SubQ: 100 units/kg/dose every 12 hours; adjust dose based on anti-Factor Xa monitoring (ACCP [Douketis 2012]). For additional information regarding anti-Factor Xa monitoring, refer to the Reference Range field.

Non-ST elevation acute coronary syndromes: For medical management when an invasive approach is not planned: SubQ: 120 units/kg (maximum dose: 10,000 units) every 12 hours with concurrent aspirin therapy; continue until patient is clinically stable (usual duration of therapy is 5 to 8 days).

Venous thromboembolism prophylaxis:

Medical patients with acute illness at moderate and high risk for venous thromboembolism: SubQ: 5,000 units once daily; continue for length of hospital stay or until patient is fully ambulatory and risk of venous thromboembolism (VTE) has diminished (ACCP [Kahn 2012]; ASCO [Key 2019]). Extended prophylaxis beyond acute hospital stay is not routinely recommended (ACCP [Kahn 2012]; Sharma 2012).

Nonorthopedic surgery (off-label use):

Patients with active cancer:

SubQ: 5,000 units started 10 to 12 hours before surgery and 5,000 units once daily thereafter (ASCO [Key 2019]).

or

SubQ: 2,500 units started 2 to 4 hours before surgery and 5,000 units once daily thereafter (ASCO [Key 2019]).

or

SubQ: 5,000 units once daily started ~6 to 12 hours after surgery (Bauer 2019a; Pai 2019a).

Note: The optimal duration of prophylaxis has not been established. It is usually given for a minimum of 7 to 10 days. Extending for up to 4 weeks may be reasonable in those undergoing major abdominal or pelvic surgery (ASCO [Key 2019]).

Patients without active cancer: Note: For patients with moderate and high risk of VTE and low risk of bleeding:

SubQ: 5,000 units ~12 hours before surgery (or the evening prior to surgery) and then 5,000 units once daily thereafter is recommended by some experts for all nonorthopedic surgeries. Alternatively, may postpone pharmacologic prophylaxis until after surgery (eg, high bleeding risk) when it is safe to initiate. Continue until fully ambulatory and risk of VTE has diminished (typically up to 10 days (ACCP [Gould 2012]; Pai 2019a).

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. In low and moderate risk patients: SubQ: 2,500 units 1 to 2 hours prior to surgery, then 2,500 units once daily thereafter.

Pregnancy (off-label use): Note: For patients at moderate and high VTE risk during antepartum and postpartum periods. Dose intensity is individualized based on risks of thrombosis and bleeding complications.

Prophylactic dose: SubQ: 5,000 units once every 24 hours (ACOG 2018).

Intermediate dose: SubQ: 5,000 units every 12 hours (ACOG 2018); however, some experts use an alternative intermediate regimen of 5,000 units once daily, increasing as pregnancy progresses to 100 units/kg once daily (Bauer 2019b; Malhotra 2018).

Adjusted dose (therapeutic): SubQ: 100 units/kg every 12 hours; or 200 units/kg once daily reserved for patients at the highest risk (eg, history of recurrent thrombosis or severe thrombophilia) (ACCP [Bates 2012]; ACOG 2018).

Note: Anticoagulation management prior to delivery is individualized. Options include replacing with unfractionated heparin (UFH) at ~36 to 37 weeks' gestation or extending to 38 to 39 weeks' gestation in patients at very low risk of delivery while on dalteparin (Bauer 2019b). In such patients, discontinue dalteparin ≥12 hours before delivery (for prophylactic doses) or ≥24 hours before delivery (for higher doses), particularly if neuraxial anesthesia is planned; may restart ≥4 to 6 hours after vaginal delivery or ≥6 to 12 hours after cesarean delivery, unless significant bleeding occurred (ACOG 2018). Anticoagulation should continue for up to 6 weeks postpartum, but potentially longer (ACCP [Bates 2012]; ACOG 2018; Bauer 2019b).

Total hip arthroplasty or total knee arthroplasty (total knee arthroplasty is an off-label use):

SubQ: 5,000 units once daily, with initial dose administered ≥12 hours preoperatively or ≥12 hours postoperatively once hemostasis is achieved (ACCP [Falck-Ytter 2012]; Pai 2019b); other regimens include 2,500 units pre- or postoperatively with a maintenance dosage of 5,000 units once daily. Optimal duration of prophylaxis is unknown, but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days (ACCP [Falck-Ytter 2012]; Dahl 1997; Lassen 1998; Pai 2019b; Sobieraj 2012); some experts suggest a duration at the higher end of range (eg, 30 days) for total hip arthroplasty and at the lower end of range (eg, 10 to 14 days) for total knee arthroplasty (Pai 2019b).

Venous thromboembolism treatment: Note: For timing of initiating oral anticoagulant, see Transitioning between anticoagulants.

Deep vein thrombosis and/or pulmonary embolism (off-label use): Inpatient treatment: SubQ: 200 units/kg once daily or 100 units/kg twice daily (AHA [Jaff 2011]; Feissinger 1996; Wells 2005). Note: In select low-risk patients, may consider outpatient treatment for the remainder of the course after first dose administered in hospital or urgent care center (ACCP [Kearon 2016]; Kovacs 2000; Erkens 2010).

Duration of therapeutic anticoagulation (first episode, general recommendations): Optimal duration of therapy is unknown and depends on many factors, such as whether provoking events were present, patient risk factors for recurrence and bleeding, and individual preference.

Provoked VTE: 3 months (provided the provoking risk factor is no longer present) (ACCP [Kearon 2016]).

Unprovoked pulmonary embolism or deep vein thrombosis (proximal or isolated distal): ≥3 months depending on risk of VTE recurrence and bleeding (ACCP [Kearon 2012]; ACCP [Kearon 2016]; ISTH [Baglin 2012]).

Note: All patients receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at periodic intervals.

Venous thromboembolism treatment in patients with active cancer: SubQ:

Initial (month 1): 200 units/kg (maximum dose: 18,000 units) once daily for 30 days, followed by maintenance therapy during months 2 to 6.

Maintenance (months 2 to 6): 150 units/kg (maximum dose: 18,000 units) once daily. Alternatively, warfarin may be used for maintenance therapy; however, meta-analyses and randomized control trials have validated the superiority of low molecular weight heparin (LMWH) over warfarin. If warfarin is to be used for maintenance therapy, overlap dalteparin with warfarin for a minimum of 5 to 7 days and continue until INR in therapeutic range for at least 48 hours (ASCO [Key 2019]; Bauer 2019c).

Maintenance beyond 6 months (off label): ACCP and ASCO guidelines for VTE prophylaxis/treatment recommend considering continuing anticoagulation beyond 6 months in selected patients due to the persistent high risk of recurrence in those with active cancer; consider risk vs benefit of bleeding and recurrence (ACCP [Kearon 2012]; ACCP [Kearon 2016]; ASCO [Key 2019]).

Dosage adjustment for thrombocytopenia: If platelet count is between 50,000 to 100,000/mm³, reduce daily dose by 2,500 units for patients weighing 46 to 82 kg and by 3,000 units for patients weighing ≥83 kg until platelet count recovers to ≥100,000/mm³. If platelet count <50,000/mm³, discontinue dalteparin until platelet count recovers to >50,000/mm³.

Venous thromboembolism treatment in pregnancy (off-label use): SubQ: 200 units/kg/dose once daily or 100 units/kg/dose every 12 hours. Some experts suggest anti-Factor Xa monitoring for dose adjustment (ACCP [Bates 2012]). For additional information regarding anti-Factor Xa monitoring, refer to the Reference Range field.

Note: Anticoagulation management prior to delivery is individualized. Options include replacing with UFH at ~36 to 37 weeks' gestation or extending to 38 to 39 weeks' gestation in patients at very low risk of delivery while on dalteparin (Bauer 2019b). In such patients, discontinue dalteparin ≥24 hours before delivery, particularly if neuraxial anesthesia is planned; may restart ≥4 to 6 hours after vaginal delivery or ≥6 to 12 hours after cesarean delivery, unless significant bleeding occurred (ACOG 2018). Optimal duration of anticoagulation is unknown. In general, total duration of anticoagulation (antepartum plus postpartum) should be at least 3 to 6 months with at least 6 weeks postpartum (ACOG 2018; Malhotra 2018).

Transitioning between anticoagulants: Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail:

Transitioning from another anticoagulant to dalteparin:

Transitioning from therapeutic IV UFH infusion to therapeutic-dose dalteparin: Discontinue UFH and begin dalteparin within 1 hour. Note: If aPTT is not in therapeutic range at the time UFH is discontinued, consult local protocol (Nutescu 2007).

Transitioning from dalteparin to another anticoagulant:

Transitioning from therapeutic-dose dalteparin to therapeutic IV UFH infusion: Start IV UFH (rate based on indication) 1 to 2 hours before the next dose of dalteparin would have been due. Note: Omit IV UFH loading dose (Nutescu 2007).

Transitioning from prophylactic dalteparin to therapeutic IV UFH: UFH should be started without delay. A UFH bolus/loading dose may be used if indicated (Nutescu 2007).

Transitioning from therapeutic-dose dalteparin to warfarin: Start warfarin and continue dalteparin until INR is within therapeutic range (Hull 2019a; Wittkowsky 2018). Note: For the treatment of VTE, overlap dalteparin with warfarin until INR is ≥2 for at least 2 measurements taken ~24 hours apart (duration of overlap is usually 4 to 5 days) (ACCP [Ageno 2012]; Hull 2019b).

Transitioning from therapeutic-dose dalteparin to a direct oral anticoagulant (DOAC): Note: In treatment of VTE, some DOACs (dabigatran, edoxaban) require 5 days of parenteral anticoagulation prior to transitioning.

General transition recommendation: Start DOAC within 2 hours prior to the next scheduled dose of dalteparin.

VTE initial treatment transition (alternative recommendation): For acute VTE, some experts start DOAC within 6 to 12 hours after the last dose of a twice-daily LMWH regimen or within 12 to 24 hours after a once-daily LMWH regimen (Hull 2019b).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Each 2,500 units of anti-Xa activity is equal to 16 mg of dalteparin (World Health Organization First International Low Molecular Weight Heparin Reference Standard). In a pediatric thrombosis treatment trial, doses for patients ≥4.4 kg were rounded to the nearest 100 unit and in obese patients, doses were based on lean body weight (O’Brien 2014); reported experience may not be appropriate for all patients (small infants, etc). For infants, avoid dosage forms that contain benzyl alcohol.

Prophylaxis, VTE: Limited data available:

Infants, Children, and Adolescents <16 years:

<50 kg: SubQ: Initial: 100 units/kg/dose every 24 hours; titrated to achieve anti-Xa levels: 0.2 to 0.4 units/mL (drawn 4 to 6 hours after the third dose); maximum dose: 5,000 units/dose.

≥50 kg: SubQ: 5,000 units every 24 hours; dose was not titrated to achieve a goal anti-Xa level.

Adolescents ≥16 years: SubQ: 5,000 units every 24 hours; dose was not titrated to achieve a goal anti-Xa level.

Note: Dosing was reported in a retrospective study of 116 pediatric patients (Warad 2015); a small trial of 10 pediatric patients reported after titration a mean dose of 92 ± 52 units/kg/dose every 24 hours achieved anti-Xa levels of 0.2 to 0.4 units/mL (drawn 4 hours after a dose) (ACCP [Monagle 2012]; Nohe 1999).

Treatment, symptomatic VTE:

Initial:

Infants to Children <2 years: SubQ: 150 units/kg/dose every 12 hours.

Children 2 years to <8 years: SubQ: 125 units/kg/dose every 12 hours.

Children ≥8 years and Adolescents: SubQ: 100 units/kg/dose every 12 hours (O’Brien 2014); a maximum dose has not been defined; based on experience in adult patients, maximum dose: 18,000 units/dose could be considered.

Dosing adjustment: Titrate dose in increments of 25 unit/kg to achieve a 4 to 6 hour post-dose target anti-Xa level: 0.5 to 1 units/mL; evaluate anti-Xa levels after the third dose (ACCP [Monagle 2012]; O’Brien 2014; Warad 2015); however, levels after the first and second doses (4 to 6 hours postdose) have also been used (O’Brien 2014); in one trial, dose adjustments were made in 10% to 20% increments (O'Brien 2014); reported median time to achieve target anti-Xa levels was 2.6 days (range: 1 to 7 days).

Data suggest that therapeutic dosing requirements per kg (units/kg/dose) are higher in infants than older pediatric patients; in one trial, the reported median effective dose in patients <2 years of age was 208 units/kg/dose; another trial reported an infant median effective dose of 180 units/kg/dose (range: 146 to 181 units/kg/dose) (O’Brien 2014; manufacturer labeling).

Duration of therapy: The exact duration of therapy for optimal anticoagulation has not been determined; sufficient pediatric data is lacking; experts suggest for provoked deep vein thrombosis (DVT) or pulmonary embolism (PE) a duration of therapy ≤3 months although, if the causative risk factor persists, a longer duration of therapy may be necessary; for unprovoked DVT/PE, a duration of anticoagulation for 6 to 12 months (ASH [Monagle 2018]).

Dosing adjustment for toxicity:

Thrombocytopenia: Infants, Children, and Adolescents:

Platelet count: 50,000 to 100,000/mm³: Reduce daily dose by 50% until platelet count recovers to ≥100,000/mm³.

Platelet count ≤50,000/mm³: Hold dalteparin therapy until platelet count recovers to above 50,000/mm³.

Dosing: Obesity

Note: Specific dosing recommendations may not be available for all indications.

Non-ST elevation acute coronary syndromes: Use actual body weight to calculate dose; dose capping at 10,000 units recommended (Nutescu 2009).

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

Venous thromboembolism treatment:

Deep vein thrombosis and/or pulmonary embolism (off-label use): Use actual body weight to calculate dose. A fixed upper dose limit is not recommended, however, increased monitoring and dosage adjustment based on anti-Factor Xa levels may be considered (Nutescu 2009). One study demonstrated similar anti-Factor Xa levels after 3 days of therapy in obese patients (>40% above ideal body weight [IBW]; range: 82 to 190 kg) compared to those ≤20% above IBW or between 20% to 40% above IBW (Wilson 2001).

Venous thromboembolism treatment in patients with active cancer: Use actual body weight to calculate dose. A fixed upper dose limit is not recommended, however, increased monitoring and dosage adjustment based on anti-Factor Xa levels may be considered (Nutescu 2009). The manufacturer recommends a maximum dose of 18,000 units per day, and ASCO guidelines on venous thromboembolism prophylaxis/treatment in patients with cancer state the optimal dose in patients >120 kg is unclear (ASCO [Key 2019]).

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

SubQ: 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 (off-label route): May administer as a bolus IV injection or as a continuous infusion; recommended concentration for infusion: 20 units/mL (Fragmin Canadian product labeling).

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

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

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

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

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

Angiotensin-Converting Enzyme Inhibitors: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Antithrombin: May enhance the anticoagulant effect of Heparins (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

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

Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. 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: Heparins (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

Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. 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. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds). Consider therapy modification

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

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

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

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

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Avoid combination

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

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): 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: Heparins (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 Heparins (Low Molecular Weight). Monitor therapy

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

Potassium-Sparing Diuretics: Heparins (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

Sulodexide: 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

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

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

Adverse Reactions

>10%:

Hematologic & oncologic: Thrombocytopenia (infants, children, and adolescents: 21% to 37%; adults: 11% to 14%; grades 3/4: ≤7%), hemorrhage (3% to 14%), bruise (infants, children, and adolescents: 12%)

Local: Bruising at injection site (infants, children, and adolescents: 30%)

1% to 10%:

Hematologic & oncologic: Major hemorrhage (1% to 4%), wound hematoma (≤3%)

Hepatic: Increased serum alanine aminotransferase (4% to 10%), increased serum aspartate aminotransferase (5% to 9%)

Local: Pain at injection site (5% to 12%), hematoma at injection site (≤6%)

Respiratory: Epistaxis (infants, children, and adolescents: 10%)

Miscellaneous: Re-operation due to bleeding (≤1%)

<1%: Gastrointestinal hemorrhage, hemoptysis, skin necrosis

Frequency not defined:

Cardiovascular: Spinal hematoma

Central nervous system: Epidural intracranial hemorrhage

Postmarketing: Alopecia, hypersensitivity reaction, nonimmune anaphylaxis, osteoporosis, postoperative wound bleeding

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. Use with extreme caution in patients at increased risk of bleeding; risk factors include 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, selective serotonin reuptake inhibitors); recent GI bleeding or ulceration; 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; can cause hyperkalemia possibly by suppressing aldosterone production. Most commonly occurs in patients with risk factors for the development of hyperkalemia (eg, renal dysfunction, concomitant use of potassium-sparing diuretics or potassium supplements, hematoma in body tissues).
• Thrombocytopenia: Cases of thrombocytopenia including thrombocytopenia with thrombosis have occurred. Monitor platelet count closely. Use is contraindicated in patients with a history of heparin-induced thrombocytopenia (HIT) or HIT with thrombosis. Interrupt or discontinue therapy in patients with platelet counts <100,000/mm³and/or thrombosis related to initiation of dalteparin, especially when associated with a positive in vitro test for antiplatelet antibodies. Use caution in patients with congenital or drug-induced thrombocytopenia or platelet defects.

Disease-related concerns:

• GI ulceration: Use with caution in patients with a history of GI ulcer.
• 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 renal impairment, especially severe renal impairment (CrCl <30 mL/minute); 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:

• Elderly: Use with caution in the elderly due to increased bleeding risks.
• Obesity: There is no consensus for adjusting/correcting the weight-based dosage of low molecular weight heparin (LMWH) for patients who are morbidly obese (BMI ≥40 kg/m²). Monitoring of anti-Factor Xa levels 4 to 6 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 LMWHs.
• 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 anti-Factor 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 myocardial infarction, or for prolonged venous thromboembolism prophylaxis in patients who will be undergoing epidural/neuraxial anesthesia.

Monitoring Parameters

Platelet count, hemoglobin, hematocrit, fecal occult blood, signs and symptoms of bleeding, anti-Factor Xa levels (as appropriate), and serum creatinine at baseline and during therapy; monitoring of PT and/or aPTT is not necessary. Routine monitoring of anti-Factor Xa activity is not required but has been utilized in patients with obesity and/or renal insufficiency. Anti-Factor Xa activity is an appropriate measure for therapeutic effect but is a poor predictor of hemorrhagic risk.

For patients >190 kg, if anti-Factor Xa monitoring is available, adjusting dose based on anti-Factor Xa levels is recommended; if anti-Factor Xa monitoring is unavailable, reduce dose if bleeding occurs (Garcia 2012; Nutescu 2009). Monitor obese patients closely for signs/symptoms of thromboembolism.

Monitoring anti-Factor Xa activity is recommended in pregnant women receiving therapeutic doses of dalteparin or when receiving dalteparin for the prevention of thromboembolism with mechanical heart valves (ACCP [Guyatt 2012]).

Pregnancy

Pregnancy Considerations

Low molecular weight heparin (LMWH) does not cross the placenta; increased risks of fetal bleeding or teratogenic effects have not been reported (ACCP [Bates 2012]).

LMWH is recommended over unfractionated heparin for the treatment of acute 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 (ACCP [Guyatt 2012]). LMWH may also be used in women with mechanical heart valves (consult current guidelines for details) (ACC/AHA [Nishimura 2014]; ACCP [Bates 2012]).

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

What is this drug used for?

• It is used to thin the blood so that clots will not form.
• It is used to treat blood clots.

Frequently reported side effects of this drug

• Injection site irritation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; 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.
• Back pain
• Paralysis
• Leaking of urine
• Leaking of stool
• Severe dizziness
• Passing out
• Confusion
• Severe headache
• Burning or numbness feeling
• Muscle weakness
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.