Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Boehringer Ingelheim International GmbH, Binger Strasse 173, D-55216, Ingelheim am Rhein, Germany
Pharmacotherapeutic group: Antithrombotic agents, enzymes
ATC code: B01AD11
Tenecteplase is a recombinant fibrin-specific plasminogen activator that is derived from native t-PA by modifications at three sites of the protein structure. It binds to the fibrin component of the thrombus (blood clot) and selectively converts thrombus-bound plasminogen to plasmin, which degrades the fibrin matrix of the thrombus. Tenecteplase has a higher fibrin specificity and greater resistance to inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.
After administration of tenecteplase dose dependent consumption of α2-antiplasmin (the fluid-phase inhibitor of plasmin) with consequent increase in the level of systemic plasmin generation have been observed. This observation is consistent with the intended effect of plasminogen activation. In comparative studies a less than 15% reduction in fibrinogen and a less than 25% reduction in plasminogen were observed in subjects treated with the maximum dose of tenecteplase (10,000 U, corresponding to 50 mg), whereas alteplase caused an approximately 50% decrease in fibrinogen and plasminogen levels. No clinically relevant antibody formation was detected at 30 days.
Patency data from the phase I and II angiographic studies suggest that tenecteplase, administered as a single intravenous bolus, is effective in dissolving blood clots in the infarct-related artery of subjects experiencing an AMI on a dose related basis.
A large scale mortality trial (ASSENT-2) in approx. 17,000 patients showed that tenecteplase is therapeutically equivalent to alteplase in reducing mortality (6.2% for both treatments, at 30 days, upper limit of the 95% CI for the relative risk ratio 1.124) and that the use of tenecteplase is associated with a significantly lower incidence of non-intracranial bleedings (26.4% vs. 28.9%, p=0.0003). This translates into a significantly lower need of transfusions (4.3% vs. 5.5%, p=0.0002). Intracranial haemorrhage occurred at a rate of 0.93% vs. 0.94% for tenecteplase and alteplase, respectively.
Coronary patency and limited clinical outcome data showed that AMI patients have been successfully treated later than 6 hours after symptom onset.
The ASSENT-4 PCI study was designed to show if in 4000 patients with large myocardial infarctions pre-treatment with full dose tenecteplase and concomitant single bolus of up to 4,000 IU unfractionated heparin administered prior to primary PCI to be performed within 60 to 180 minutes leads to better outcomes than primary PCI alone. The trial was prematurely terminated with 1667 randomised patients due to a numerically higher mortality in the facilitated PCI group receiving tenecteplase. The occurrence of the primary endpoint, a composite of death or cardiogenic shock or congestive heart failure within 90 days, was significantly higher in the group receiving the exploratory regimen of tenecteplase followed by routine immediate PCI: 18.6% (151/810) compared to 13.4% (110/819) in the PCI only group, p=0.0045. This significant difference between the groups for the primary endpoint at 90 days was already present in-hospital and at 30 days.
Numerically all of the components of the clinical composite endpoint were in favour of the PCI only regimen: death: 6.7% vs. 4.9% p=0.14; cardiogenic shock: 6.3% vs. 4.8% p=0.19; congestive heart failure: 12.0% vs. 9.2% p=0.06 respectively. The secondary endpoints re-infarction and repeat target vessel revascularisation were significantly increased in the group pre-treated with tenecteplase: re-infarction: 6.1% vs. 3.7% p=0.0279; repeat target vessel revascularisation: 6.6% vs. 3.4% p=0.0041. The following adverse events occurred more frequently with tenecteplase prior to PCI: intracranial haemorrhage: 1% vs. 0% p=0.0037; stroke: 1.8% vs. 0% p<0.0001; major bleeds: 5.6% vs. 4.4% p=0.3118; minor bleeds: 25.3% vs. 19.0% p=0.0021; blood transfusions: 6.2% vs. 4.2% p=0.0873; abrupt vessel closure: 1.9% vs. 0.1% p=0.0001.
The STREAM study was designed to evaluate the efficacy and safety of a pharmaco-invasive strategy versus a strategy of standard primary PCI in patients presenting with ST elevation acute myocardial infarction within 3 hours of onset of symptoms not able to undergo primary PCI within one hour of first medical contact. The pharmaco-invasive strategy consisted of early fibrinolytic treatment with bolus tenecteplase and additional antiplatelet and anticoagulant therapy followed by angiography within 6-24 hours or rescue coronary intervention.
The study population consisted of 1,892 patients randomised by means of an interactive voice response system. The primary endpoint, a composite of death or cardiogenic shock or congestive heart failure or re-infarction within 30 days, was observed in 12.4% (116/939) of the pharmaco-invasive arm versus 14.3% (135/943) in the primary PCI arm (relative risk 0.86 (0.68-1.09)).
Single components of the primary composite endpoint for the pharmaco-invasive strategy versus primary PCI respectively were observed with the following frequencies:
| Pharmaco-invasive (n=944) | Primary PCI (n=948) | p | |
|---|---|---|---|
| Composite death, shock, congestive heart failure, re-infarction | 116/939 (12.4%) | 135/943 (14.3%) | 0.21 |
| All-cause mortality | 43/939 (4.6%) | 42/946 (4.4%) | 0.88 |
| Cardiogenic shock | 41/939 (4.4%) | 56/944 (5.9%) | 0.13 |
| Congestive heart failure | 57/939 (6.1%) | 72/943 (7.6%) | 0.18 |
| Re-infarction | 23/938 (2.5%) | 21/944 (2.2%) | 0.74 |
| Cardiac mortality | 31/939 (3.3%) | 32/946 (3.4%) | 0.92 |
The observed incidence of major and of minor non-ICH bleeds were similar in both groups:
| Pharmaco-invasive (n=944) | Primary PCI (n=948) | p | |
|---|---|---|---|
| Major non-ICH bleed | 61/939 (6.5%) | 45/944 (4.8%) | 0.11 |
| Minor non-ICH bleed | 205/939 (21.8%) | 191/944 (20.2%) | 0.40 |
Incidence of total strokes and intracranial haemorrhage:
| Pharmaco-invasive (n=944) | Primary PCI (n=948) | p | |
|---|---|---|---|
| Total stroke (all types) | 15/939 (1.6%) | 5/946 (0.5%) | 0.03* |
| Intracranial haemorrhage | 9/939 (0.96%) | 2/946 (0.21%) | 0.04** |
| Intracranial haemorrhage after protocol amendment to half dose in patients ≥75 years: | 4/747 (0.5%) | 2/758 (0.3%) | 0.45 |
* the incidences in both groups are those expected in STEMI patients treated by fibrinolytics or primary PCI (as observed in previous studies).
** the incidence in the pharmaco-invasive group is as expected for fibrinolysis with tenecteplase (as observed in previous studies).
After the dose reduction of tenecteplase by half in patients ≥75 years there was no further intracranial hemorrhage (0 of 97 patients) (95% CI: 0.0-3.7) versus 8.1% (3 of 37 patients) (95% CI: 1.7-21.9) prior to dose reduction. The bounds of the confidence interval of the observed incidences prior and after dose reduction are overlapping.
In patients ≥75 years the observed incidence of the primary efficacy composite end point for the pharmaco-invasive strategy and primary PCI were as follows: before dose reduction 11/37 (29.7%) (95% CI: 15.9- 47.0) versus 10/32 (31.3%) (95% CI: 16.1-50.0), after dose reduction: 25/97 (25.8%) (95% CI: 17.4-35.7) versus 25/88 (24.8%) (95% CI: 19.3-39.0). In both groups the bounds of the confidence interval of the observed incidences prior and post dose reduction are overlapping.
Tenecteplase is an intravenously administered, recombinant protein that activates plasminogen. Following intravenous bolus administration of 30 mg tenecteplase in patients with acute myocardial infarction, the initially estimated tenecteplase plasma concentration was 6.45 ± 3.60 μg/mL (mean ± SD). The distribution phase represents 31% ± 22% to 69% ± 15% (mean ± SD) of the total AUC following the administration of doses ranges from 5 to 50 mg.
Data on tissue distribution were obtained in studies with radioactively labelled tenecteplase in rats. The main organ to which tenecteplase distributed was the liver. It is not known whether and to which extent tenecteplase binds to plasma proteins in humans. The mean residence time (MRT) in the body is approximately 1 h and the mean (± SD) volume of distribution at the steady-state (Vss) ranged from 6.3 ± 2 L to 15 ± 7 L.
Tenecteplase is cleared from circulation by binding to specific receptors in the liver followed by catabolism to small peptides. Binding to hepatic receptors is, however, reduced compared to native t-PA, resulting in a prolonged half-life.
After single intravenous bolus injection of tenecteplase in patients with acute myocardial infarction, tenecteplase antigen exhibits biphasic elimination from plasma. There is no dose dependence of tenecteplase clearance in the therapeutic dose range. The initial, dominant half-life is 24 ± 5.5 (mean ±SD) min, which is 5 times longer than native t-PA. The terminal half-life is 129 ± 87 min, and plasma clearance is 119 ± 49 ml/min.
Increasing body weight resulted in a moderate increase of tenecteplase clearance, and increasing age resulted in a slight decrease of clearance. Women exhibit in general lower clearance than men, but this can be explained by the generally lower body weight of women.
The dose linearity analysis based on AUC suggested that tenecteplase exhibits non-linear pharmacokinetics in the dose range studied, i.e. 5 to 50 mg.
Because elimination of tenecteplase is through the liver, it is not expected that renal dysfunction will affect its the pharmacokinetics. This is also supported by animal data. However, the effect of renal and hepatic dysfunction on pharmacokinetics of tenecteplase in humans has not been specifically investigated. Accordingly, there is no guidance for the adjustment to tenecteplase dose in patients with hepatic and severe renal insufficiency.
Intravenous single dose administration in rats, rabbits and dogs resulted only in dose-dependent and reversible alterations of the coagulation parameters with local haemorrhage at the injection site, which was regarded as a consequence of the pharmacodynamic effect of tenecteplase. Multiple-dose toxicity studies in rats and dogs confirmed these above-mentioned observations, but the study duration was limited to two weeks by antibody formation to the human protein tenecteplase, which resulted in anaphylaxis.
Safety pharmacology data in cynomolgus monkeys revealed reduction of blood pressure followed by changes of ECG, but these occurred at exposures that were considerably higher than the clinical exposure.
With regard to the indication and the single dose administration in humans, reproductive toxicity testing was limited to an embryotoxicity study in rabbits, as a sensitive species. Tenecteplase induced total litter deaths during the mid-embryonal period. When tenecteplase was given during the mid- or late-embryonal period maternal animals showed vaginal bleeding on the day after the first dose. Secondary mortality was observed 1-2 days later. Data on the foetal period are not available.
Mutagenicity and carcinogenicity are not expected for this class of recombinant proteins and genotoxicity and carcinogenicity testing were not necessary.
No local irritation of the blood vessel was observed after intravenous, intra-arterial or paravenous administration of the final formulation of tenecteplase.
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