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Renal Patients: Efficacy and Safety Profile
Schmid P et al. Swiss Med Wkly 2009;139:438–4521.
A critical review of published data regarding the pharmacokinetic properties of low molecular weight heparin (LMWH) used for the treatment of patients with renal insufficiency.
In general, LMWH are more effective and have a lower bleeding risk than UFH. In addition, LMWH have bioavailability of >85% after s.c. injection; in contrast, s.c. administered UFH has bioavailability of 15–40% with wide variability. LMWHs such as Fragmin may be considered for patients with severe renal insufficiency for up to 10 days, with careful monitoring.
LMWH may be suitable for patients with severe renal insufficiency. Careful monitoring of bioaccumulation (anti-Xa levels) is necessary.
Douketis J et al. Arch Intern Med 2008;168:1805–1812 (DIRECT)2.
Prospective, multicentre, single-arm, open-label clinical trial to determine if DVT prophylaxis with Fragmin conferred an excessive anticoagulant effect in critically-ill patients with severe renal insufficiency (N=138). 5,000 IU Fragmin was administered o.d. in patients with CrCl <30 mL/min; pharmacokinetic properties were assessed by serial anti-Xa levels measured on days 3, 10 and 17.
Trough and peak anti-Xa levels, measured on days 3, 10 and 17.
The median duration of Fragmin exposure was 7 (IQR = 4–12) days. 120 patients had at least 1 trough anti-Xa level, and none had bioaccumulation, defined by a trough anti-Xa level higher than 0.40 IU/mL (0%; 95% CI, 0%–3.0%).
Asymptomatic DVT developed in 5.1% of patients (n=7; 95% CI, 2.5%–10.1%); major bleeding occurred in 7.2% of patients (n=10; 95% CI, 4.0%–12.8%), all with trough anti-Xa levels of 0.18 IU/mL or lower. Mean CrCl at baseline and at the end of Fragmin prophylaxis was 18.9 mL/min and 28.4 mL/min, respectively.
DVT prophylaxis with Fragmin for 7 days was not associated with bioaccumulation or excessive anticoagulant effect.
Monreal M et al. Am J Med 2006;119:1073–1079 (RIETE)3.
RIETE is a prospective registry of patients with symptomatic acute VTE. This analysis retrospectively analysed the effect of renal insufficiency on the incidence of fatal PE and fatal bleeding within 15 days of diagnosis. Patients (N=10,526) were grouped as follows: 88.0% had a CrCl >60 mL/min (n=9,234), 6.7% had a CrCl 30–60 mL/min (n=704), and 5.6% had a CrCl <30 mL/min (n=588). Mean initial daily doses of LMWH and UFH were similar in the 3 patient groups.
Incidence of death due to PE or bleeding.
The incidence of major bleeding was significantly higher in the abnormal groups (CrCl 30–60 mL/min and CrCl <30 mL/min), whereas the incidence of VTE recurrences was similar in all three subgroups.
The incidence of fatal PE during the study was 1.0%, 2.6%, and 6.6%, across the CrCl >60 mL/min, CrCl 30-60 mL/min and CrCl <30 mL/min groups, respectively. In addition, the use of UFH was associated with a significantly higher risk of fatal PE compared with LMWH. Fatal bleeding occurred in 0.2%, 0.3% and 1.2% of patients from the CrCl >60 mL/min, CrCl 30–60 mL/min and CrCl <30 mL/min groups, respectively.
Multivariate analysis confirmed that decreasing CrCl, cancer and immobility for 4 days or more were independently associated risk factors for fatal PE and fatal bleeding.
Patients with VTE and renal insufficiency had an increased incidence of both fatal PE and fatal bleeding, but the risk of fatal PE far exceeded that of fatal bleeding.
Schmid P et al. J Thromb Haemost 2009;7:552–5584.
Prospective cohort study, comparing pharmacokinetic data for Fragmin for up to three weeks in patients with varying degrees of renal insufficiency. Patients were grouped according to renal function: normal (GFR =60 mL/min/1.73m2; N=18), mild (GFR 30–59 mL/min/1.73m2; N=15) or severe (GFR <30 mL/min/1.73m2; N=9). Fragmin was injected s.c once daily at a prophylactic dose. Peak anti-Xa activity levels were measured 4 hours after injection on Day 1 and every third day up to 3 weeks.
Peak anti-Xa levels and adjusted anti-Xa levels (adjustment being carried out for dose and body weight).
A total of 42 patients could be analysed during a median of 10 days (IQR = 4–13, range 1–20). In all groups, adjusted peak anti-Xa levels were not significantly different on Day 10 compared with Day 1. No bioaccumulation >30% (the statistical detection threshold) could be found up to Day 10 in any of the groups.
The use of Fragmin at a prophylactic dose was not associated with a bioaccumulation >30%, even in patients with severe renal insufficiency during a median follow-up of 10 days.
Shprecher AR et al. Pharmacotherapy 2005;25:817–8225.
Prospective, single-centre, open-label, unblinded, comparative study to determine the relationship between impaired renal function and anti-Xa activity in patients requiring therapeutic anticoagulation. Fragmin at a dose of ~100 U/kg was administered s.c. twice daily to patients with renal insufficiency (CrCl < 40mL/min, N=11) and patients without renal insufficiency (CrCl >80 mL/min, N=11). This study assessed whether anti-Xa activity was meaningfully greater in the group with renal insufficiency vs the group with normal renal function.
Peak anti-Xa levels.
Mean ± SD levels were similar for patients with and without renal insufficiency: 0.47 ± 0.25 and 0.55 ± 0.20 U/mL respectively. This difference was not statistically significant. No trend was identified for anti-Xa activity levels by BMI. No serious adverse events occurred and no patients were withdrawn from the study.
Fragmin was well tolerated in patients with renal insufficiency and in control subjects; there was no significant difference in peak anti-Xa activity between both groups.
Tincani E et al. Haematologica 2006;91:976–9796.
Prospective cohort study to determine the incidence of Fragmin bioaccumulation and bleeding complications during thromboprophylaxis in elderly patients (N=115) with renal failure admitted to hospital with an acute medical illness. Fragmin was administered s.c. once daily, at a dose of 5,000 IU in patients at high VTE risk, and 2,500 IU in patients at low risk. Anti-Xa activity was determined before the first dosage and on Day 6 of treatment; bleeding was assessed daily.
Anti-Xa activity on Day 6 of Fragmin treatment.
Anti-Xa levels before the first dose of Fragmin were undetectable and there was no relationship between the degree of renal insufficiency and the peak anti-Xa level at Day 6.
There were no major bleeding events; no symptomatic VTE events and no asymptomatic DVT were recorded (95% CI, 0% to 2.5%). Of the 115 patients, 3 (2.7%) had minor haemorrhages (95% CI, 0.6% to 6.7%).
Fragmin thromboprophylaxis in elderly patients admitted with an acute medical illness who have renal insufficiency was associated with a low risk of both bioaccumulation and bleeding.
Fragmin (dalteparin sodium) 10,000 IU/0.4ml solution for injection
Fragmin (dalteparin sodium) 10,000 IU/1 ml solution for injection
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Fragmin (dalteparin sodium) 12,500 IU/0.5ml solution for injection
Fragmin (dalteparin sodium) 15,000 IU/0.6ml solution for injection
Fragmin (dalteparin sodium) 18,000 IU/0.72ml solution for injection
Fragmin (dalteparin sodium) 2500 IU solution for injection
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Fragmin (dalteparin sodium) 7,500 IU/0.3 ml solution for injection
Fragmin (dalteparin sodium) Graduated Syringe 10,000 IU/ml Solution for Injection
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PP-PFE-GBR-2688. December 2020