1000 variants of rt‑PA were evaluated, resulting in the identification of key structure‑function relationships.1 The three targeted alterations which differentiate TNKase from the rt‑PA molecule contribute to the following pharmacological improvements:
||Increased Fibrin Specificity
|TNKase has 8-10 times the fibrin selectivity in vitro of Activase® (alteplase)1 (the clinical significance of increased fibrin specificity has not been established)2
||Greater Resistance to Plasminogen Activator Inhibitor-1 (PAI-1)2
|TNKase is more resistant to PAI-1 in vitro, relative to Activase. PAI-1 is a natural fibrinolysis inhibitor that can disrupt plasminogen activation
|The initial half-life of TNKase is approximately 3 to 6 times that of Activase in vivo, allowing it to be delivered in one single bolus over 5 seconds
The clinical significance of increased fibrin specificity, greater resistance to PAI-1, and long plasma half-life have not been established.
Activase® (alteplase) is indicated for use in acute
myocardial infarction (AMI) for the reduction of mortality and reduction of the incidence of
Limitation of Use: The risk of stroke may outweigh the benefit
produced by thrombolytic therapy in patients whose AMI puts them at low risk for death or heart
Important Safety Information
Do not administer Activase to treat acute myocardial infarction in the
following situations in which the risk of bleeding is greater than the potential benefit: active
internal bleeding; history of recent stroke; recent (within 3 months) intracranial or intraspinal
surgery or serious head trauma; presence of intracranial conditions that may increase the risk of
bleeding (e.g. some neoplasms, arteriovenous malformations, or aneurysms); bleeding diathesis;
and current severe uncontrolled hypertension.
Warnings and Precautions
Activase can cause significant, sometimes fatal internal or external
bleeding, especially at arterial and venous puncture sites. Avoid intramuscular injections and
trauma to the patient. Perform venipunctures carefully and only as required. Fatal cases of
hemorrhage associated with traumatic intubation in patients administered Activase have been
reported. Aspirin and heparin have been administered concomitantly with and following infusions
of Activase in the management of AMI. Because heparin, aspirin, or Activase may cause bleeding
complications, carefully monitor for bleeding, especially at arterial puncture sites. If serious
bleeding occurs, terminate the Activase infusion, and treat properly.
In the following conditions, the risks of bleeding with Activase are
increased and should be weighed against the anticipated benefits: recent major surgery or
procedure; cerebrovascular disease; recent intracranial hemorrhage; recent gastrointestinal or
genitourinary bleeding; recent trauma; hypertension; acute pericarditis; subacute bacterial
endocarditis; hemostatic defects including those secondary to severe hepatic or renal disease;
significant hepatic dysfunction; pregnancy; diabetic hemorrhagic retinopathy or other hemorrhagic
ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site;
advanced age; and patients currently receiving oral anticoagulants, or any other condition in
which bleeding constitutes a significant hazard or would be particularly difficult to manage
because of its location.
Hypersensitivity, including urticarial/anaphylactic reactions, have been
reported. Rare fatal outcome for hypersensitivity was reported. Angioedema has been observed
during and up to 2 hours after infusion in patients treated for acute ischemic stroke and acute
myocardial infarction. In many cases, patients received concomitant angiotensin converting enzyme
inhibitors. Monitor patients during and for several hours after infusion for hypersensitivity. If
signs of hypersensitivity occur, e.g. anaphylactoid reaction or angioedema develops, discontinue
Activase and promptly institute appropriate therapy (e.g., antihistamines, intravenous
The use of thrombolytics can increase the risk of thrombo-embolic events
in patients with high likelihood of left heart thrombus, such as patients with mitral stenosis
or atrial fibrillation. Activase has not been shown to treat adequately underlying deep vein
thrombosis in patients with PE. Consider the possible risk of re-embolization due to the lysis
of underlying deep venous thrombi in this setting.
Cholesterol embolism, sometimes fatal, has been reported rarely in
patients treated with thrombolytic agents; the true incidence is unknown. It is associated with
invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery)
and/or anticoagulant therapy.
Coagulation Tests May be Unreliable during Activase Therapy
Coagulation tests and/or measures of fibrinolytic activity may be
unreliable during Activase therapy unless specific precautions are taken to prevent
in vitro artifacts. When present in blood at pharmacologic concentrations, Activase
remains active under in vitro conditions, which can result in degradation of fibrinogen
in blood samples removed for analysis.
The most frequent adverse reaction associated with Activase AMI therapy
Please see full Prescribing Information
for additional Important Safety Information.
TNKase® (tenecteplase) is indicated for
use in the reduction of mortality associated with acute myocardial infarction
(AMI). Treatment should be initiated as soon as possible after the onset of AMI
Important Safety Information
TNKase therapy in patients with AMI is contraindicated in
the following situations because of an increased risk of bleeding: active
internal bleeding; history of cerebrovascular accident; intracranial or
intraspinal surgery, or trauma within 2 months; intracranial neoplasm,
arteriovenous malformation, or aneurysm; known bleeding diathesis; and
severe uncontrolled hypertension.
The most common complication encountered during TNKase
therapy is bleeding. Should serious bleeding (not controlled by local
pressure) occur, any concomitant heparin or antiplatelet agents should be
discontinued immediately and treated appropriately.
In clinical studies of TNKase, patients were treated with
both aspirin and heparin. Heparin may contribute to the bleeding risks
associated with TNKase. The safety of the use of TNKase with other
antiplatelet agents has not been adequately studied. Intramuscular injections
and nonessential handling of the patient should be avoided for the first few
hours following treatment with TNKase.
The risk of bleeding may be increased in the following
conditions and should be weighed against the anticipated benefits: recent
major surgery, cerebrovascular disease, recent gastrointestinal or
genitourinary bleeding, recent trauma, hypertension, acute pericarditis, subacute
bacterial endocarditis, hemostatic defects, severe hepatic dysfunction, pregnancy,
diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, septic
thrombophlebitis or occluded AV cannula at seriously infected site, advanced
age, patients currently receiving oral anticoagulants, recent administration
of GP IIb/IIIa inhibitors, and any other condition in which bleeding
constitutes a significant hazard or would be particularly difficult to manage
because of its location.
The use of thrombolytics can increase the risk of thrombo-embolic events in patients
with high likelihood of left heart thrombus, such as patients with mitral stenosis or
Cholesterol embolism has been reported rarely in patients
treated with all types of thrombolytic agents; the true incidence is unknown.
This serious condition, which can be lethal, is also associated with invasive
vascular procedures (e.g., cardiac catheterization, angiography, vascular
surgery) and/or anticoagulant therapy.
Coronary thrombolysis may result in arrhythmias associated
with reperfusion. It is recommended that anti-arrhythmic therapy for
bradycardia and/or ventricular irritability be available when TNKase is
Use with Percutaneous Coronary Intervention (PCI)
In patients with large ST-segment elevation myocardial
infarction, physicians should choose either thrombolysis or PCI as the primary
treatment strategy for reperfusion.
Standard management of myocardial infarction should be
implemented concomitantly with TNKase treatment. In the event of serious bleeding,
heparin and antiplatelet agents should be discontinued immediately.
Anaphylactoid reactions associated with the administration
of TNKase are rare and can be caused by hypersensitivity to the active substance
tenecteplase or to any of the excipients. If symptoms of hypersensitivity occur,
appropriate therapy should be initiated.
Drug and Drug/Laboratory Test Interactions
Formal interaction studies of TNKase with other drugs have
not been performed. Patients studied in clinical trials of TNKase were routinely
treated with heparin and aspirin.
During TNKase therapy, results of coagulation tests and/or
measures of fibrinolytic activity may be unreliable unless specific precautions are
taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in
blood in pharmacologic concentrations, remains active under in vitro conditions. This
can lead to degradation of fibrinogen in blood samples removed for analysis.
The most frequent adverse reaction associated with TNKase
Should serious bleeding occur, concomitant heparin and
antiplatelet therapy should be discontinued. Death or permanent disability
can occur in patients who experience stroke or serious bleeding episodes. For
TNKase-treated patients in ASSENT-2, the incidence of intracranial hemorrhage was 0.9%
and incidence of any stroke was 1.8%. The incidence of all strokes, including intracranial
bleeding, increases with advancing age.
Please see full Prescribing Information for additional
Important Safety Information.
Bennett WF, Paoni NF, Keyt BA, et al. High resolution analysis of functional determinants on human tissue-type plasminogen activator. J Biol Chem. 1991;266:5191-5201.|
|2. ||Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen activator in acute myocardial infarction: results of the Thrombolysis Myocardial Infarction (TIMI) 10A dose-ranging trial. Circulation. 1997;95:351-356.|