Tnkase Information
Tnkase (Tenecteplase) Description
Tnkase (Tenecteplase) is a tissue plasminogen activator (tPA) produced by recombinant DNA technology using an established mammalian cell line (Chinese Hamster Ovary cells). Tenecteplase is a 527 amino acid glycoprotein developed by introducing the following modifications to the complementary DNA (cDNA) for natural human tPA: a substitution of threonine 103 with asparagine, and a substitution of asparagine 117 with glutamine, both within the kringle 1 domain, and a tetra-alanine substitution at amino acids 296–299 in the protease domain. Cell culture is carried out in nutrient medium containing the antibiotic gentamicin (65 mg/L). However, the presence of the antibiotic is not detectable in the final product (limit of detection is 0.67 µg/vial). Tnkase (Tenecteplase) is a sterile, white to off-white, lyophilized powder for single intravenous (IV) bolus administration after reconstitution with Sterile Water for Injection (SWFI), USP. Each vial of Tnkase (Tenecteplase) nominally contains 52.5 mg Tenecteplase, 0.55 g L-arginine, 0.17 g phosphoric acid, and 4.3 mg polysorbate 20, which includes a 5% overfill. Each vial will deliver 50 mg of Tenecteplase.
Tnkase (Tenecteplase) Clinical Pharmacology
In patients with acute myocardial infarction (AMI), Tnkase (Tenecteplase) administered as a single bolus exhibits a biphasic disposition from the plasma. Tenecteplase was cleared from the plasma with an initial half-life of 20 to 24 minutes. The terminal phase half-life of Tenecteplase was 90 to 130 minutes. In 99 of 104 patients treated with Tenecteplase, mean plasma clearance ranged from 99 to 119 mL/min.
The initial volume of distribution is weight related and approximates plasma volume. Liver metabolism is the major clearance mechanism for Tenecteplase.
Tnkase (Tenecteplase) Clinical Studies
ASSENT-2 was an international, randomized, double-blind trial that compared 30-day mortality rates in 16,949 patients assigned to receive an IV bolus dose of Tnkase (Tenecteplase) or an accelerated infusion of Activase (Alteplase). Eligibility criteria included onset of chest pain within 6 hours of randomization and ST-segment elevation or left bundle branch block on electrocardiogram (ECG). Patients were to be excluded from the trial if they received GP IIb/IIIa inhibitors within the previous 12 hours. Tnkase (Tenecteplase) was dosed using actual or estimated weight in a weight-tiered fashion as described in . All patients were to receive 150–325 mg of aspirin administered as soon as possible, followed by 150–325 mg daily. Intravenous heparin was to be administered as soon as possible: for patients weighing ≤67 kg, heparin was administered as a 4000 unit IV bolus followed by infusion at 800 U/hr; for patients weighing >67 kg, heparin was administered as a 5000 unit IV bolus followed by infusion at 1000 U/hr. Heparin was continued for 48 to 72 hours with infusion adjusted to maintain aPTT at 50–75 seconds. The use of GP IIb/IIIa inhibitors was discouraged for the first 24 hours following randomization. The results of the primary endpoint (30-day mortality rates with non-parametric adjustment for the covariates of age, Killip class, heart rate, systolic blood pressure and infarct location) along with selected other 30-day endpoints are shown in Table 1.
Rates of mortality and the combined endpoint of death or stroke among pre-specified subgroups, including age, gender, time to treatment, infarct location, and history of previous myocardial infarction, demonstrate consistent relative risks across these subgroups. There was insufficient enrollment of non-Caucasian patients to draw any conclusions regarding relative efficacy in racial subsets.
Rates of in-hospital procedures, including percutaneous transluminal coronary angioplasty (PTCA), stent placement, intra-aortic balloon pump (IABP) use, and coronary artery bypass graft (CABG) surgery, were similar between the Tnkase (Tenecteplase) and Activase(Alteplase) groups.
TIMI 10B was an open-label, controlled, randomized, dose-ranging, angiography study which utilized a blinded core laboratory for review of coronary arteriograms. Patients (n = 837) presenting within 12 hours of symptom onset were treated with fixed doses of 30, 40, or 50 mg of Tnkase (Tenecteplase) or the accelerated infusion of Activase and underwent coronary arteriography at 90 minutes. The results showed that the 40 mg and 50 mg doses were similar to accelerated infusion of Activase in restoring patency. TIMI Grade 3 flow and TIMI Grade 2/3 flow at 90 minutes are shown in Table 2. The exact relationship between coronary artery patency and clinical activity has not been established.
The angiographic results from TIMI 10B and the safety data from ASSENT-1, an additional uncontrolled safety study of 3,235 Tnkase (Tenecteplase) -treated patients, provided the framework to develop a weight-tiered Tnkase (Tenecteplase) dose regimen. Exploratory analyses suggested that a weight-adjusted dose of 0.5 mg/kg to 0.6 mg/kg of Tnkase (Tenecteplase) resulted in a better patency to bleeding relationship than fixed doses of Tnkase (Tenecteplase) across a broad range of patient weights.
The Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT 4 PCI) was a Phase IIIb/IV study designed to to assess the safety and effectiveness of a strategy of administering full dose Tnkase (Tenecteplase) with a single bolus of 4000 U of unfractionated heparin in patients with ST segment elevation AMI, in whom primary percutaneous coronary intervention (PCI) was planned, but in whom a delay of 1–3 hours was anticipated before PCI. The trial was prematurely terminated with 1667 randomized patients (75 of whom were treated in the United States) due to a numerically higher mortality in the patients receiving Tnkase (Tenecteplase) prior to primary PCI versus PCI without Tnkase (Tenecteplase) (median time from randomization to balloon of 115 minutes). The incidence of the 90‑day primary endpoint, a composite of death or cardiogenic shock or congestive heart failure (CHF) within 90 days, was 18.6% in patients treated with Tnkase (Tenecteplase) plus PCI versus 13.4% in those treated with PCI alone (p=0.0055; OR 1.39 (95% C.I. 1.11–1.74)).
There were trends toward worse outcomes in the individual components of the primary endpoint between Tnkase (Tenecteplase) plus PCI versus PCI alone (mortality 6.7% vs. 5.0%, respectively; cardiogenic shock 6.1% vs. 4.8%, respectively; and CHF 12.1% vs. 9.4%, respectively). In addition, there were trends towards worse outcomes in recurrent MI (6.1% vs. 3.5%, respectively; p=0.03) and repeat target vessel revascularization (6.6% vs. 3.6%, respectively; p=0.005) in patients receiving Tnkase (Tenecteplase) plus PCI versus PCI alone.
There was no difference in in‑hospital major bleeding between the two groups (5.6% vs. 4.4% for Tnkase (Tenecteplase) plus PCI vs. PCI alone, respectively). For patients treated with Tnkase (Tenecteplase) plus PCI, in‑hospital rates of intracranial hemorrhage and total stroke were similar to those observed in previous trials (0.97% and 1.8%, respectively); however, none of the patients treated with PCI alone experienced a stroke (ischemic, hemorrhagic or other).
Tnkase (Tenecteplase) Indications And Usage
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 symptoms (see ).
Tnkase (Tenecteplase) Contraindications
Tnkase (Tenecteplase) therapy in patients with acute myocardial infarction is contraindicated in the following situations because of an increased risk of bleeding (see ):
Tnkase (Tenecteplase) Warnings
The most common complication encountered during Tnkase (Tenecteplase) therapy is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into two broad categories:
Should serious bleeding (not controlled by local pressure) occur, any concomitant heparin or antiplatelet agents should be discontinued immediately.
In clinical studies of Tnkase (Tenecteplase) , patients were treated with both aspirin and heparin. Heparin may contribute to the bleeding risks associated with Tnkase (Tenecteplase) . The safety of the use of Tnkase (Tenecteplase) with other antiplatelet agents has not been adequately studied (see ). Intramuscular injections and nonessential handling of the patient should be avoided for the first few hours following treatment with Tnkase (Tenecteplase) . Venipunctures should be performed and monitored carefully.
Should an arterial puncture be necessary during the first few hours following Tnkase (Tenecteplase) therapy, it is preferable to use an upper extremity vessel that is accessible to manual compression. Pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.
Each patient being considered for therapy with Tnkase (Tenecteplase) should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy. In the following conditions, the risk of Tnkase (Tenecteplase) therapy may be increased and should be weighed against the anticipated benefits:
Tnkase (Tenecteplase) Adverse Reactions
The most frequent adverse reaction associated with Tnkase (Tenecteplase) is bleeding (see ).
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 (Tenecteplase) -treated patients in ASSENT-2, the incidence of intracranial hemorrhage was 0.9% and any stroke was 1.8%. The incidence of all strokes, including intracranial bleeding, increases with increasing age (see).
In the ASSENT-2 study, the following bleeding events were reported (see ).
Non-intracranial major bleeding and the need for blood transfusions were lower in patients treated with Tnkase (Tenecteplase) .
Types of major bleeding reported in 1% or more of the patients were hematoma (1.7%) and gastrointestinal tract (1%). Types of major bleeding reported in less than 1% of the patients were urinary tract, puncture site (including cardiac catheterization site), retroperitoneal, respiratory tract, and unspecified. Types of minor bleeding reported in 1% or more of the patients were hematoma (12.3%), urinary tract (3.7%), puncture site (including cardiac catheterization site) (3.6%), pharyngeal (3.1%), gastrointestinal tract (1.9%), epistaxis (1.5%), and unspecified (1.3%).
The following adverse reactions have been reported among patients receiving Tnkase (Tenecteplase) in clinical trials. These reactions are frequent sequelae of the underlying disease, and the effect of Tnkase (Tenecteplase) on the incidence of these events is unknown.
These events include cardiogenic shock, arrhythmias, atrioventricular block, pulmonary edema, heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial reinfarction, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, thrombosis, embolism, and electromechanical dissociation. These events can be life-threatening and may lead to death. Nausea and/or vomiting, hypotension, and fever have also been reported.
Tnkase (Tenecteplase) Dosage And Administration
Tnkase (Tenecteplase) is for intravenous administration only. The recommended total dose should not exceed 50 mg and is based upon patient weight.
A single bolus dose should be administered over 5 seconds based on patient weight. Treatment should be initiated as soon as possible after the onset of AMI symptoms (see ).
The safety and efficacy of Tnkase (Tenecteplase) have only been investigated with concomitant administration of heparin and aspirin as described in .
THE 10 mL SYRINGE WITH TWINPAK DUAL CANNULA DEVICE
NOTE
Tnkase (Tenecteplase) How Supplied
Tnkase (Tenecteplase) is supplied as a sterile, lyophilized powder in a 50 mg vial under partial vacuum. Each 50 mg vial of Tnkase (Tenecteplase) is packaged with one 10 mL vial of Sterile Water for Injection, USP for reconstitution, the B-D 10 mL syringe with TwinPak Dual Cannula Device, and three alcohol prep pads. NDC 50242-038-61.
Tnkase (Tenecteplase)
