Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Pfizer Limited, Ramsgate Road, Sandwich KENT, CT13 9NJ, United Kingdom
Dalteparin sodium is a low molecular weight heparin fraction (weight average molecular weight of 6000 Daltons (range between 5,600 and 6,400 Daltons)) produced from porcine-derived heparin sodium.
Dalteparin sodium is an antithrombotic agent, which acts mainly through its ability to potentiate the inhibition of Factor Xa and thrombin by antithrombin. It has a relatively higher ability to potentiate Factor Xa inhibition than to prolong plasma clotting time (APTT).
Compared with standard, unfractionated heparin, dalteparin sodium has a reduced adverse effect on platelet function and platelet adhesion, and thus has only a minimal effect on primary haemostasis. Still some of the antithrombotic properties of dalteparin sodium are thought to be mediated through the effects on vessel walls or the fibrinolytic system.
In a randomised, actively controlled, double-blind trial in 1500 patients undergoing hip replacement surgery (North American Fragmin Trial), both pre-operative and post-operative Fragmin were found to be superior to warfarin (see table below). There was a numerical superiority for pre-operative Fragmin over post-operative Fragmin. Thus in patients where the risk of bleeding is perceived to be too great for pre-operative Fragmin administration other means of reducing thromboembolic risk such as post-operative Fragmin administration may be considered.
Incidence of verified thromboembolic events in ITT efficacy population within 6 ± 2 post-operative days.
| Phase 1 | Pre-op. dalteparin | Post-op dalteparin | Warfarin | |||
|---|---|---|---|---|---|---|
| n/N | % | n/N | % | n/N | % | |
| DVT and or PE | 37/338* | 10.9 | 44/336* | 13.1 | 81/338 | 24.0 |
| Proximal DVT | 3/354 | 0.8 | 3/358 | 0.8 | 11/363 | 3.0 |
* p <0.001 vs. warfarin (Cochran-Mantel-Haenszel test, two-sided)
Abbreviations: n/N = number of patients affected/number of efficacy-evaluable patients; post-op. = treatment at earliest 4 hours after surgery; pre-op. = treatment within 2 hours before surgery.
There is limited safety and efficacy information on the use of dalteparin in paediatric patients. If dalteparin is used in these patients, anti-Xa levels should be monitored.
The largest prospective study investigated the efficacy, safety and relation of dose to plasma anti-Xa activity of dalteparin in prophylaxis and therapy of arterial and venous thrombosis in 48 paediatric patients (Nohe et al, 1999).
Nohe et al (1999) Study Demographics and Trial Design:
| Trial design | Patients | Diagnosis | Indication, Fragmin Dose, Target anti-Xa, Duration | ||
|---|---|---|---|---|---|
| Single-center, open label trial; (n=48) | Age: 31 week preterm to 18 years Gender: 32 males, 16 females | Arterial or venous thrombosis; PVOD; PPH | Prophylaxis: (n=10) 95 ± 52 anti-Xa IU/kg sc qd; 0.2 to 0.4 IU/mL 3-6 months | Primary Therapy: (n=25) 129 ± 43 anti-Xa IU/kg sc qd; 0.4 to 1.0 IU/mL 3-6 months | Secondary Therapy: (n=13) 129 ± 43 anti-Xa IU/kg sc qd; 0.4 to 1.0 IU/mL 3-6 months |
In this study, no thromboembolic events occurred in the 10 patients receiving dalteparin for thromboprophylaxis. In the 23 patients given dalteparin for primary antithrombotic therapy of arterial or venous thrombosis, complete recanalization was seen in 7/23 (30%), partial recanalization in 7/23 (30%) and no recanalization in 9/23 (40%). In the 8 patients administered dalteparin for secondary antithrombotic therapy following successful thrombolysis, recanalisation was maintained or improved. In the 5 patients receiving dalteparin for secondary therapy following failed thrombolysis, no recanalization was seen. Minor bleeding, reported in 2/48 children (4%), resolved after dose reduction. Patient platelet counts ranged from 37,000/μl to 574,000/μl. The authors attributed platelet counts below normal (150,000/μl) to immunosuppressive therapy. A reduction in platelet count ≥50% of the initial value, a sign of heparin-induced thrombocytopenia type 2 (HIT 2), was not observed in any patient. For both prophylaxis and therapy groups, the dalteparin doses (anti-Xa IU/kg) required to achieve target anti-Xa activities (IU/ml) were inversely related to age (r2=0.64, P=0.017; r2=0.13, P=0.013). The predictability of the anticoagulant effect with weight-adjusted doses appears to be reduced in children compared to adults, presumably due to altered plasma binding (see section 5.2).
The half-life following iv. and s.c. administration is 2 hours and 3.5-4 hours respectively, twice that of unfractionated heparin.
The bioavailability following s.c. injection is approximately 87 per cent and the pharmacokinetics are not dose dependent. The half life is prolonged in uraemic patients as dalteparin sodium is eliminated primarily through the kidneys.
In patients with chronic renal insufficiency requiring haemodialysis, the mean terminal hal-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU dalteparin was 5.7 ± 2.0 hours, i.e. considerably longer than values observed in healthy volunteers, therefore, greater accumulation can be expected in these patients.
Infants less than approximately 2 to 3 months of age or <5 kg have increased LMWH requirements per kg likely due to their larger volume of distribution. Alternative explanations for the increased requirement of LMWH per body weight in young children include altered heparin pharmacokinetics and/or a decreased expression of anticoagulant activity of heparin in children due to decreased plasma concentrations of antithrombin.
The acute toxicity of dalteparin sodium is considerably lower than that of heparin. The only significant finding, which occurred consistently throughout the toxicity studies after subcutaneous administration of the higher dose levels was local haemorrhage at the injection sites, dose-related in incidence and severity. There was no cumulative effect on injection site haemorrhages.
The haemorrhagic reaction was reflected in dose related changes in the anticoagulant effects as measured by APTT and anti-Factor Xa activities.
It was concluded that dalteparin sodium did not have a greater osteopenic effect than heparin since at equivalent doses the osteopenic effect was comparable.
The results revealed no organ toxicity irrespective of the route of administration, doses or duration of treatment. No mutagenic effect was found. No embryotoxic or teratogenic effects and no effect on fertility, reproductive capacity or peri- and post natal development was shown.
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