Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Actavis Group PTC ehf, Reykjavíkurvegi 76-78, 220 Hafnarfjordur, Iceland
Pharmacotherapeutic group: antithrombotic agent
ATC Code: B01AD07
Reteplase is a recombinant plasminogen activator that catalyzes the cleavage of endogenous plasminogen to generate plasmin. This plasminogenolysis occurs preferentially in the presence of fibrin. Plasmin in turn degrades fibrin, which is the main component of the matrix of thrombi, thereby exerting its thrombolytic action.
Reteplase (10 + 10 U) dose-dependently reduces plasma fibrinogen levels by about 60 to 80%. The fibrinogen level normalises within 2 days. As with other plasminogen activators a rebound phenomenon then occurs during which fibrinogen levels reach a maximum within 9 days and remain elevated for up to 18 days.
Reductions of plasma levels of plasminogen and α2-antiplasmin normalise within 1 to 3 days. Coagulation factor V, clotting factor VIII, α2-macroglobulin, and C1-esterase inhibitor are only slightly reduced and normalise within 1 to 2 days. Plasminogen activator inhibitor 1 (PAI-1) activity can be reduced to around zero, but rapidly normalises within two hours showing a rebound phenomenon. Prothrombin activation fragment 1 levels and thrombin-antithrombin III-complexes increase during thrombolysis indicating thrombin production of which the clinical relevance is unknown.
A large comparative mortality trial (INJECT) in approx. 6000 patients showed that reteplase reduced the incidence of heart failure (secondary efficacy criterion) in a significant manner and was at least equally effective in terms of reducing mortality (primary efficacy criterion) when compared to streptokinase. In two clinical trials aiming primarily at coronary artery patency (RAPID I and II) reteplase was associated with higher early patency rates (primary efficacy criterion), as well as with a lower incidence of heart failure (secondary efficacy criterion) than alteplase (3 hour and “accelerated” dosage regimens). A clinical trial in approximately 15 000 patients comparing reteplase with the accelerated dose regimen of alteplase (GUSTO III) (2:1 randomisation reteplase: alteplase) did not show statistically different results for the primary endpoint of 30-day mortality (reteplase: 7.47%, alteplase 7.23%, p=0.61) or for the combined endpoint of 30-day mortality and non-fatal disabling stroke (reteplase: 7.89%, alteplase 7.88%, p=0.99). Overall stroke rates were 1.64% in the reteplase and 1.79% in the alteplase group. In the reteplase group, 49.4% of these strokes were fatal and 27.1% were disabling. In the alteplase group 33.0% were fatal and 39.8% were disabling.
Following intravenous bolus injection of 10 + 10 U in patients with acute myocardial infarction reteplase antigen is distributed in plasma with a dominant half-life (t½α) of 18 ± 5 min and eliminated with a terminal half-life (t½ß) of 5.5 hours ± 12.5 min at a clearance rate of 121 ± 25 ml/min. Reteplase activity is cleared from the plasma at a rate of 283 ± 101 ml/min, resulting in a dominant half-life (t½α) of 14.6 ± 6.7 min and a terminal half-life (t½ß) of 1.6 hours ± 39 min. Only minor amounts of reteplase were immunologically detected in the urine. Exact data on the main elimination routes for reteplase in humans are not available and the consequences of hepatic or renal insufficiency are not known. Experiments in rats indicate that the liver and the kidneys are the main organs of active uptake and lysosomal degradation.
Additional studies in human plasma samples in vitro suggest that complexation with C1-inactivator, α2-antiplasmin and α2-antitrypsin contributes to the inactivation of reteplase in plasma. The relative contribution of the inhibitors to inactivation of reteplase decreases as follows: C1-inactivator > α2- antiplasmin > α2-antitrypsin.
The half-life of reteplase was increased in patients with AMI as compared to healthy volunteers. An additional increase of half-life of activity in patients with myocardial infarction and severely impaired liver and renal function cannot be excluded, but no clinical data of pharmacokinetics of reteplase in these patients are available. Animal data show that in case of severely impaired renal function with a pronounced increase in serum creatinine and serum urea an increase in half-life of reteplase has to be expected. Mild impairment of renal function did not significantly affect the pharmacokinetic properties of reteplase.
Acute toxicity studies were performed in rats, rabbits and monkeys Subacute toxicity studies were performed in rats, dogs and monkeys. The predominant acute symptom after single high doses of reteplase in rats and rabbits was transient apathy shortly after injection. In cynomolgus monkeys, the sedative effect ranged from slight apathy to unconsciousness, caused by a reversible dose-related drop in blood pressure. There was increased local haemorrhage at the injection site.
Subacute toxicity studies did not reveal any unexpected adverse events. In dogs repeated dosing of the human peptide reteplase led to immunologic-allergic reactions. Genotoxicity of reteplase was excluded by a complete battery of tests at different genetic end points in vitro and in vivo.
Reproductive toxicity studies were performed in rats (fertility and embryo-foetotoxicity study including a littering phase) and in rabbits (embryo-foetotoxicity study, dose-range finding only). In rats, a species insensitive to the pharmacological effects of reteplase, there were no adverse effects on fertility, embryo-foetal development and offspring. In rabbits, vaginal bleedings and abortions possibly associated to prolonged haemostasis, but no foetal abnormalities were noted. A pre- and postnatal toxicity study was not performed with reteplase.
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