ZIBOR 3.500 IU Solution for injection Ref.[10842] Active ingredients: Bemiparin

The pharmacokinetic properties of bemiparin have been determined by measuring the plasma anti-Xa activity using the amydolitic method; it is based on reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard (National Institute for Biological Standards and Control, (NIBSC).

The absorption and elimination processes follow a linear kinetic of the 1st order.

Absorption

Bemiparin sodium is rapidly absorbed following subcutaneous injection and the bioavailability is estimated to be 96%. The maximum plasma anti-Xa effect at prophylactic doses of 2,500 IU and 3,500 IU occurs 2 to 3 hours after subcutaneous injection of bemiparin, reaching peak activities in the order of 0.34 + (0.08) and 0.45 + (0.07) IU antiXa/ml, respectively. Anti-IIa activity was not detected at these doses. The maximum plasma anti-Xa effect at treatment doses of 5,000 IU, 7,500 IU, 10,000 IU and 12,500 IU occurs 3 to 4 hours after subcutaneous injection of bemiparin, reaching peak activities in the order of 0.54 + (0.06), 1.22 + (0.27), 1.42 + (0.19) and 2.03 + (0.25) IU anti-Xa/ml, respectively. Anti-IIa activity of 0.01 IU/ml was detected at doses of 7,500 IU, 10,000 IU and 12,500 IU.

Elimination

Bemiparin administered in the dose range of 2,500 IU to 12,500 IU has an approximate half-life of between 5 and 6 hours, and should therefore be administered once daily.

There are currently no data available with regards to plasma protein binding, biotransformation and excretion of bemiparin in humans.

Elderly: the results from a pharmacokinetic analysis of the clinical trial conducted in healthy young volunteers and elderly (> 65 years) show that there are no significant differences in the kinetic profile of bemiparin between young and elderly when renal function is normal.

Renal impairment: (see sections: 4.2 Posology and method of administration and 4.4 Special warnings and precautions for use) the results from a pharmacokinetic analysis of the clinical trial conducted in young, elderly and subjects with varying degrees of renal impairment (creatinine clearance <80 ml/min), administering multiple prophylactic doses (3,500 IU/24 h) and a single therapeutic dose (115 IU/kg) of bemiparin, showed a correlation between creatinine clearance and most pharmacokinetic parameters of anti-Xa activity. In addition, it was shown that exposure to bemiparin (based on AUC of anti-Xa activity) was significantly higher in the group of volunteers with severe renal impairment (creatinine clearance <30 ml/min) compared to the rest of groups of volunteers.

On the other hand, pharmacokinetic simulations were conducted to evaluate the profile of bemiparin after administration of ten consecutive daily doses. The mean maximum anti-Xa activity (Amax) simulated after 10 prophylactic doses (3,500 IU/24 h) was in all groups between 0.35 and 0.60 IU anti-Xa/ml; however, in the group of severe renal impairment (creatinine clearance <30 ml/min) one subject showed a value of Amax=0.81 IU anti-Xa/ml after the tenth dose. Simulating a dose reduction up to 2,500 IU/24 h, the model predicted values of Amax lower than 0.60 IU anti-Xa/ml (mean value of Amax= 0.42 IU anti-Xa/ml) for all volunteers from the group of severe renal impairment. In addition, the predicted mean of Amax after 10 therapeutic doses (115 IU/kg/24 h) was between 0.89 and 1.22 IU anti-Xa/ml in all groups; also, a volunteer from the severe renal impairment group showed a value of Amax=2.09 IU anti-Xa/ml after the last administration. When it was simulated a dose adjustment up to 75% of the therapeutic dose (86.25 IU/kg/24 h) it was predicted an Amax of 1.60 IU anti-Xa/ml for the aforementioned volunteer, and at the same time the mean Amax (0.91 IU anti-Xa/ml) of the severe renal impairment group remained within the range observed for the rest of the groups without dose adjustment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction.

Acute and repeated dose toxicity studies following subcutaneous administration of bemiparin in animals have revealed alterations consisting essentially in reversible, dose-dependent haemorrhagic lesions at the injection site. These were considered to result from exaggerated pharmacological activity.

In the studies of reproductive toxicity performed with bemiparin in pregnant rats and rabbits, between days 6 and 18 of the pregnancy, no mortality was recorded among the females treated with bemiparin. The main clinical signs recorded were subcutaneous haematomas that were attributable to a pharmacological effect of the test item. No treatment-related embryotoxic effect neither external, skeletal and/or visceral alterations were recorded in the examination of fetuses.