Dalteparin

Generic name
Dalteparin
Brand name
ATC Code
B01AB04
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Dalteparin

Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Pharmacokinetics in children

Dalteparin has a longer half-life than heparin.

Children younger than about 2 to 3 months or lighter than 5 kg need more low molecular weight heparin (LMWH) per kilogram, probably because of their greater volume of distribution. Alternative explanations for the increased LMWH requirement per unit bodyweight in young children include altered heparin pharmacokinetics and/or decreased expression of the anticoagulant activity of heparin in children due to reduced plasma concentrations of antithrombin.

The pharmacokinetics (PK) of dalteparin was described using a 1-compartment model with linear absorption and elimination, and PK parameters are shown the table below. After adjusting for body weight, clearance (CL/F) decreased with increasing age, while the volume of distribution at steady-state (Vd/F) remained the same. The mean elimination half-life increased with age. [SmPC]

Parameter 0-8 weeks 8 wk- 2 years 2-8 years 8-12 years 12-19 years
Nr of patients 6 13 14 11 45
Age median (range) 0,06 (0,04-0,14) 0,5 (0,2-1,91) 4,47 (2,01-7,6) 9,62 (8,01-10,5) 15,9 (12,0-19,5)
Clearance ml/uur/kg (SD) 55,8 (3,91) 40,4 (8,49) 26,7 (4,75) 22,4 (3,40) 18,8 (3,01)
Vd ml/kg (SD) 181 (15,3) 175 (55,3) 160 (25,6) 165 (27,3) 171 (38,9)
T½ hours (SD) 2,25 (0,173) 3,02 (0,688) 4,27 (1,05) 5,11 (0,509) 6,28 (0,937)

 

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Prophylaxis for thromboembolic complications
  • Subcutaneous
    • Full-term neonates and children 0 years up to 2 years
      [3] [4] [7]
      • 150 IU/kg/day in 1 dose

      • Titrate the dose based on the concentrations. See warnings and precautions section.

    • 2 years up to 8 years
      [3] [4] [7]
      • 125 IU/kg/day in 1 dose. Max: 2.500 IU/day. in patients with normal risk. In high-risk patients (including COVID-19 patients) max 5000 IU/day.

      • Titrate the dose based on the concentrations. See warning and precaution section.

    • 8 years up to 18 years
      [3] [4] [7]

      • Normal risk: 2500 E once daily
        High risk (including COVID-19 patients): 5000 E once daily

      • Titrate the dose based on the concentrations. See warnings and precautions section.
Treatment of venous thrombosis
  • Subcutaneous
    • 0 years up to 2 years
      [2] [3] [4] [5]
      • 300 IU/kg/day in 2 doses.

      • Titrate the dose based on the concentrations. See warnings and precautions section.

    • 2 years up to 8 years
      [3] [4] [5]
      • 250 IU/kg/day in 2 doses.

      • Titrate the dose based on the concentrations. See warnings and preacutions section.

    • 6 years up to 12 years
      [3]
      • 248 IU/kg/day in 2 doses.

      • Titrate the dose based on the concentrations. Check the anti-Xa level 4 hours after giving LMWH. The target anti-factor Xa level is 0.5 – 1.0 IU/ml. Dissolve the dose in a minimum of 0.2 ml.

    • 8 years up to 18 years
      [3] [4] [7]
      • 200 IU/kg/day in 1 - 2 doses. Max: 18.000 IU/day.
        • Two times daily dosing in patients with increased risk of bleeding. 
        • Adjust dose based on the concentrations. See warnings and precautions section. 
Haemodialysis
  • Intravenous
    • < 15 kg
      [1]
      • At the start of haemodialysis 1.500 IU/dose, once only.
    • 15 up to 30 kg
      [1]
      • At the start of haemodialysis 2.500 IU/dose, once only.
    • 30 up to 45 kg
      [1]
      • At the start of haemodialysis 5.000 IU/dose, once only.
    • ≥ 45 kg
      [1]
      • At the start of haemodialysis 5.000 - 10.000 IU/dose, once only.

Renal impaiment in children > 3 months

Prophylaxis thromboembolic complications:

  • GFR ≥10: adjustment of dose is not necessary.
  • GFR <10: general advice is not given.

Treatment venous thrombosis:

  • GFR ≥ 50: adjusting dose is not necessary.
  • GFR 30-50: 1st dose 100% of normal single dose, then 75% of normal single dose, interval between two doses: 12 hours; if used for more than 3 days dose according to anti-Xa levels.
  • GFR 10-30: 1st dose 100% of normal single dose, then 50% of normal single dose, interval between doses: 12 hours; if used for more than 3 days, dose according to anti-Xa levels.
  • GFR <10: general advice is not given.
Clinical consequences

With impaired renal function, accumulation of dalteparin may occur. This increases the risk of bleeding.

Clinical implications:
Bleeding.

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Bleeding, HITT syndrome (heparin-induced thrombocytopenia and thrombosis)

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Note: administer protamine for overdoses; this however, has a partial effect – consult a haematologist. The cephalin time is not a good measure of anticoagulation.

1 mg protamine antagonated the effect of 100 E dalteparine.

Anti-FXa levels and monitoring:
Anti-FXa level, measured 4 hours after dose, measure first anti-FXa after 3 doses.
Target anti-FXa level
therapeutic:
in BID dosing LMWH: 0.5 - 1.0 U / mL;
in once daily dosing LMWH: 1.0-2.0 U / mL;
prophylactic: 0.1-0.4 U / mL,
For COVID-19 patients admitted to the intensive care: <0,7 U / ml

> 40 kg: in general no anti-FXa monitoring necessary, except for sick children, co-medication and / or poor kidney function

After possible dose adjustment, it is not necessary to wait for 3 doses. This can be agreed in consultation with the local laboratory. When therapeutic level is reached, further monitoring is only necessary in neonates, severely ill patients, and patients during asparaginase use (due to decreasing antithrombin).

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

ANTITHROMBOTIC AGENTS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

Heparin group
B01AB05
B01AB01
B01AB06
Platelet aggregation inhibitors excl. heparin
B01AC06

References

  1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
  2. CBO, Richtlijn Diagnostiek, preventie en behandeling van veneuze trombo-embolie en secundaire preventie van arteriele trombose, www.cbo.nl, 2009, 161
  3. Klaassen ILM. et al, Are low-molecular-weight heparins safe and effective in children? A systematic review., Blood Rev, 2018, DOI: 10.1016/j.blre.2018.06.003
  4. Nederlandse Vereniging voor Kindergeneeskunde, sectie kinderhematologie, Richtlijn Diagnostiek en behandeling van veneuze trombo-embolische complicaties bij neonaten en kinderen tot 18 jaar, https://hematologienederland.nl/kwaliteit/werkboek-kinderhematologie/, 2020, Jan , Revisie 1
  5. O'Brien SH, et al, Multicenter dose-finding and efficacy and safety outcomes in neonates and children treated with dalteparin for acute venous thromboembolism, J Thromb Haemost., 2014, 12(11), 1822-5
  6. NKFK Werkgroep nierfunctiestoornissen, Extrapolatie van KNMP risico analyse "Verminderde nierfunctie" voor volwassenen naar kinderen, 20 Dec 2021
  7. Pfizer BV, SmPC Fragmin (RVG 12786) 10-06-2022, www.geneesmiddeleninformatiebank.nl

Changes

Therapeutic Drug Monitoring


Overdose