Nadroparin Calcium1

Abstract

Nadroparin calcium is a low molecular weight heparin with a mean molecular weight of 4.5kD. Compared with unfractionated heparin, nadroparin calcium has a greater ratio of anti-factor Xa/ anti-factor IIa activity. Nadroparin calcium has a longer half-life and greater bioavailability than unfractionated heparin and can be administered by subcutaneous injection once daily for prophylaxis and twice daily for treatment. In clinical trials, nadroparin calcium has been shown to be at least as effective as unfractionated heparin in preventing deep venous thrombosis (DVT) after various surgical procedures including major orthopaedic and abdominal surgery, and in maintaining the patency of the extracorporeal circulation in adults and children undergoing haemodialysis. Nadroparin calcium is well tolerated, the most common adverse event associated with its use being the development of minor haematoma at the operative incision site. In postmarketing surveillance data to date, the incidence of major haemorrhage related to nadroparin calcium use has been very low (< 1%). Nadroparin calcium has also been associated with a very low incidence of thrombocytopenia (< 0.001%). Thus, nadroparin calcium is an effective alternative to unfractionated heparin in the prophylaxis or treatment of thromboembolic venous events, with the advantages of more convenient administration and a lower incidence of thrombocytopenia. Nadroparin calcium is a low molecular weight heparin prepared from porcine heparin by nitrous acid depolymerisation. Nadroparin calcium has a mean molecular weight of 4.5kD (range 1 to 10kD) and is less polydisperse than unfractionated heparin, with 50% of molecules having a molecular weight of 4 to 5.5kD. The anti-factor Xa activity of low molecular weight heparins has been standardised through development of the First International Standard, but nadroparin calcium is most often quantified in anti-factor Xa Institute Choay units (IGU); 1 ICU is approximately equivalent to 0.4 international standard units (IU). The standardised units provide a useful means of quantifying the activity of a single low molecular weight heparin, but anti-factor Xa activity provides only a partial measure of clinical activity and does not facilitate cross-referencing the activities of chemically distinct low molecular weight heparins. In a nonhuman primate model, the extent and time course of nadroparin calcium-induced inhibition of factor IIa and factor Xa activity was related to route of administration. In platelet-poor plasma, nadroparin calcium is less potent gravimetrically than unfractionated heparin at inhibiting thrombin generation; nadroparin calcium 7500 ICU (3000IU)/day subcutaneously resulted in insignificant inhibition of factor Ha activity. In vitro evaluation demonstrated that 20 mg/L of nadroparin calcium caused near maximal inhibition of factor Xa generation in healthy volunteers. In animal models low doses of nadroparin calcium appear to inhibit thrombus growth more effectively than equigravimetric doses of unfractionated heparin; in high doses both nadroparin calcium and unfractionated heparin actually decreased thrombus size. While in some patients nadroparin calcium appeared to prevent the postoperative decrease in plasminogen levels, overall nadroparin calcium did not appear to have a global effect on fibrinolysis. Pharmacokinetic parameters of nadroparin calcium have generally been determined by assessment of anti-factor Xa activity in human plasma. Subcutaneous or intravenous administration of nadroparin calcium results in a dose-dependent increase in plasma anti-factor Xa activity, and in most cases large inter-patient variability is reported. The maximal plasma anti-factor Xa activity is approximately 3-fold higher following intravenous compared with subcutaneous administration, but the bioavailability of subcutaneous nadroparin calcium is estimated to be more than 98%. Some accumulation appears to be possible following twice daily subcutaneous administration of nadroparin calcium 7500 ICU, but this is minimised when nadroparin calcium 7500 ICU is given once daily. The apparent volume of distribution of nadroparin calcium in healthy volunteers is between 3 and 6.77 L/kg. The plasma elimination half-life of anti-factor Xa activity is between 2.2 and 3.6 hours following intravenous or subcutaneous administration. Plasma clearance is thought to involve nonsaturable renal mechanisms; it is significantly reduced in patients with varying degrees of renal impairment compared with healthy subjects (0.6 to 0.8 vs 1.17 L/ h), although it is uncertain whether there is a significant correlation between creatinine clearance and elimination half-life of anti-factor Xa activity. Accumulation of anti-factor Xa activity could potentially complicate nadroparin calcium therapy in patients with renal impairment. Nadroparin calcium does not appear to cross the placenta and has been shown to have no effect on anti-factor Xa or anti-factor Ha activity in the fetal circulation. Nadroparin calcium administered subcutaneously is effective for prevention of DVT and pulmonary embolus (PE) in both surgical and medical patients. Nadroparin calcium 100 to 200 ICU/ kg daily appears to produce a dose-proportional reduction in the incidence of DVT (detected either noninvasively, by fibrinogen uptake testing, or by phlebography) following orthopaedic surgery; however, to minimise the risk of haemorrhage, the minimal effective dosage should be employed. Compared with activated partial thromboplastin time (aPTT) adjusted-dose unfractionated heparin prophylaxis, nadroparin calcium 100 ICU/kg for 3 days followed by 150 ICU/ kg for 4 days resulted in a comparable global incidence of total phlebographically-detected DVT (12.6 vs 16%), but nadroparin calcium significantly reduced the incidence of proximal venous thrombosis (2.9 vs 13.1%); the incidence of haemorrhagic complications was similar between the 2 treatment groups. Prophylactic use of nadroparin calcium 7500 ICU/day following general surgery has been associated with an incidence of DVT (detected by radiolabelled-fibrinogen uptake tests) of 2.5 to 3.4%; in most studies this incidence increased to 6.3 to 6.8% in patients with malignancy. Proximal venous thromboses were detected in 0 to 0.5% of patients receiving nadroparin calcium and in one study the rate of proximal thrombosis was significantly lower in nadroparin calcium recipients (0.4%) compared with patients receiving unfractionated heparin (1.4%). The number of patients treated with nadroparin calcium for prophylaxis of DVT following other surgical procedures is too small to allow conclusions to be made regarding efficacy, but the preliminary results demonstrated a favourable risk: benefit ratio following nadroparin calcium prophylaxis in both ophthalmological and neurological surgery. In general medical inpatients, prophylactic use of nadroparin calcium 7500 ICU/day resulted in a slightly lower incidence of DVT (detected by clinical diagnosis, ultrasound or fibrinogen uptake tests and confirmed by phlebography) and PE than placebo (2.93 vs 3.94% and 0.81 vs 1.36%, respectively). The incidence of DVT with nadroparin calcium (0 to 2%) was similar to that with unfractionated heparin (0.8 to 2%). As treatment for established DVT, subcutaneous nadroparin calcium 225 ICU/kg twice daily improved the extent of venous thrombosis determined by phlebography compared with adjusted-dose intravenous unfractionated heparin. Subcutaneous nadroparin calcium 225 ICU/kg twice daily tended to decrease the recurrence rate of DVT or PE compared with unfractionated heparin; however, the difference between the 2 treatment groups was not statistically significant. Nadroparin calcium 400 ICU/kg daily subcutaneously was as effective as intravenous unfractionated heparin in the treatment of established PE. Nadroparin calcium is effective at maintaining the extracorporeal circulation in adult and paediatric patients undergoing haemodialysis; a single intravenous bolus of 150 to 250 ICU/kg for adults and 300 ICU/kg for children (adjusted to achieve clinical efficacy) appeared to have an efficacy comparable to that of individualised dosages of unfractionated heparin. Patients with heparin-induced thrombocytopenia and positive nadroparin calcium platelet aggregation tests in vitro should not be treated with nadroparin calcium. Laboratory monitoring of anti-factor Xa activity is not required during prophylaxis with nadroparin calcium unless a patient has severe renal impairment. During treatment of established DVT or PE it is recommended that factor Xa activity is monitored to assess the individual response to nadroparin calcium, although monitoring may not prove to be necessary. Nadroparin calcium appears to be well tolerated. Treatment was discontinued in 0.46% of patients as a result of adverse effects during prophylactic therapy. Haemorrhage is the most common adverse effect occurring in 4% of patients, but in most cases haemorrhagic effects were minor and did not require dosage adjustment or withdrawal of therapy. During postmarketing surveillance of an estimated 15 million patient treatments, nadroparin calcium was attributed with causing thrombocytopenia in < 0.001% of patients. Therefore, although the incidence of thrombocytopenia appears to be very low, it is recommended that the platelet count be monitored twice weekly. Postmarketing surveillance also reported cutaneous necrosis in isolated cases. In clinical trials where nadroparin calcium was administered as treatment of DVT or as prophylaxis in medical patients, nadroparin calcium tended to cause slightly fewer haemorrhagic adverse effects than unfractionated heparin (0 to 2.3% vs 3.2 to 5%); however, these trials were not large enough to demonstrate any significant superiority of nadroparin calcium in this regard. When given as prophylaxis following surgical procedures, nadroparin calcium was associated with a risk of postoperative bleeding comparable to that observed following prophylaxis with unfractionated heparin, and greater than that following placebo. For prevention of DVT following orthopaedic surgery the recommended dosage of nadroparin calcium is 100 ICU/kg/day subcutaneously beginning 12 hours preoperatively and continued for 3 days, after which the dosage should be increased to 150 ICU/kg/day for at least 4 more days. For prevention of venous thromboembolic disease following general surgery subcutaneous administration of nadroparin calcium 7500 ICU daily is recommended; this dosage also appears to be effective in the prevention of DVT following ophthalmological and neurological surgery and in medical patients. Nadroparin calcium 450 ICU/kg/day is recommended for the treatment of DVT and appears to be effective in the treatment of PE. Nadroparin calcium 150 to 300 ICU/kg intravenously has been used to maintain the patency of the catheter and dialyser in the extra-corporeal circulation in adults and children undergoing haemodialysis; however, the dosage must be individualised. Nadroparin calcium dosage may need to be reduced in patients with renal impairment.