Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Nordic Group B.V., Siriusdreef 22, 2132 WT Hoofddorp, the Netherlands
Pharmacotherapeutic group: Antihemorrhagics, proteinase inhibitors
ATC code: B02AB01
Aprotinin is a broad-spectrum protease inhibitor which has antifibrinolytic properties. By forming reversible stoichiometric enzyme-inhibitor complexes, aprotinin acts as an inhibitor of human trypsin, plasmin, plasma kallikrein and tissue kallikrein, thus inhibiting fibrinolysis.
It also inhibits the contact phase activation of coagulation which both initiates coagulation and promotes fibrinolysis.
Data from a global pool of placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) surgery showed that the incidence of serum creatinine elevations >0.5 mg/dL above pre-treatment levels was statistically higher at 9.0% (185/2047) in the full-dose aprotinin group compared with 6.6% (129/1957) in the placebo group, with an odds ratio of 1.41 (1.12-1.79). In the majority of instances, post-operative renal dysfunction was not severe and reversible. The incidence of serum creatinine elevations >2.0 mg/dL above baseline was similar (1.1% vs 0.8%) in both the full-dose aprotinin and placebo group, with an odds ratio of 1.16 (0.73-1.85) (see section 4.4).
The in-hospital mortality in a pool of randomized, clinical trials is summarized in the table below:
| In-hospital Mortality in a pool of Randomized Clinical Trials (Population: All Global CABG Patients Valid for Safety) | |||||
|---|---|---|---|---|---|
| Population | Full-Dose Aprotinin | Placebo | Odds Ratio (95% CI) | ||
| n/N | % | n/N | % | ||
| All CABG | 65/2249 | 2.9 | 55/2164 | 2.5 | 1.09 (0.78, 1.52) |
| Primary CABG | 36/1819 | 2.0 | 39/1785 | 2.2 | 0.92 (0.62, 1.38) |
| Repeat CABG | 22/276 | 8.0 | 13/255 | 5.1 | 1.47 (0.75, 2.87) |
After intravenous injection, rapid distribution of aprotinin occurs into the total extracellular space, leading to an initial decrease in plasma aprotinin concentration with a half-life of 0.3-0.7 h. At later time points, (i.e. beyond 5 hours post-dose) there is a terminal elimination phase with a half-life of about 5-10 hours.
The placenta is probably not absolutely impermeable to aprotinin, but permeation appears to take a very slow course.
The aprotinin molecule is metabolised to shorter peptides or amino acids by lysosomal activity in the kidney. In man, urinary excretion of active aprotinin accounts for less than 5% of the dose. After receiving injections of 131I-aprotinin healthy volunteers excreted within 48 hours 25-40% of the labelled substance as metabolites in the urine. These metabolites lacked enzyme-inhibitory activity.
No pharmacokinetic studies are available in patients with terminal renal insufficiency. Studies in patients with renal impairment revealed no clinically significant pharmacokinetic alterations or obvious side effects. A special dose adjustment is not warranted.
In rats, guinea-pigs, rabbits and dogs, high doses >150,000 KIU/kg) injected quickly caused a blood pressure reduction of varying magnitude, which rapidly subsided.
In rat intravenous studies, daily doses of up to 80,000 KIU/kg produced no maternal toxicity, embryotoxicity, or foetotoxicity. Daily doses of up to 100,000 KIU/kg did not interfere with the growth and development of the young and doses of 200,000 KIU/kg/day were not teratogenic. In rabbits, daily intravenous doses of 100,000 KIU/kg produced no evidence of maternal toxicity, embryotoxicity, foetotoxicity or teratogenicity.
Aprotinin gave a negative mutagenic response in the salmonella/microsome and B.subtilis DNA damage system.
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