Thrombolytic Agent

Reduce mortality associated with acute myocardial infarction

C

Administer to pregnant women only if the potential benefits justify the risk to the fetus. Exercise caution when administering to a nursing woman.

Hypersensitivity to tenecteplase or any component; active internal bleeding, history of stroke, intracranial/intraspinal surgery or trauma within 2 months, intracranial neoplasm, arteriovenous malformation or aneurysm, known bleeding diathesis, severe uncontrolled hypertension

Stop antiplatelet agents and heparin if serious bleeding occurs. Avoid I.M. injections and nonessential handling of the patient for a few hours after administration. Monitor for bleeding complications. Venipunctures should be performed carefully and only when necessary. If arterial puncture is necessary, then use an upper extremity that can be easily compressed manually. For the following conditions, the risk of bleeding is higher with use of tenecteplase and should be weighed against the benefits: Recent major surgery, cerebrovascular disease, recent GI or GU bleed, recent trauma, uncontrolled hypertension (systolic BP greater than or equal to 180 mm Hg and/or diastolic BP greater than or equal to 110 mm Hg), suspected left heart thrombus, acute pericarditis, subacute bacterial endocarditis, hemostatic defects, severe hepatic dysfunction, pregnancy, hemorrhagic diabetic retinopathy or other hemorrhagic ophthalmic conditions, septic thrombophlebitis or occluded arteriovenous cannula at seriously infected site, advanced age (see Usual Dosing, Elderly), anticoagulants, recent administration of GP IIb/IIIa inhibitors. Coronary thrombolysis may result in reperfusion arrhythmias. Caution with readministration of tenecteplase. Safety and efficacy have not been established in pediatric patients. Cholesterol embolism has rarely been reported.

As with all drugs which may affect hemostasis, bleeding is the major adverse effect associated with tenecteplase. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the dosage administered, concurrent use of multiple agents which alter hemostasis, and patient predisposition. Rapid lysis of coronary artery thrombi by thrombolytic agents may be associated with reperfusion-related arterial and/or ventricular arrhythmias. The incidence of stroke and bleeding increase in patients >65 years.

Hematologic: Bleeding (22% minor: ASSENT-2 trial)

Local: Hematoma (12% minor)

1% to 10%:

Central nervous system: Stroke (2%)

Gastrointestinal: GI hemorrhage (1% major, 2% minor), epistaxis (2% minor)

Genitourinary: GU bleeding (4% minor)

Hematologic: Bleeding (5% major: ASSENT-2 trial)

Local: Bleeding at catheter puncture site (4% minor), hematoma (2% major)

Respiratory: Pharyngeal bleeding (3% minor)

<1%: Intracranial hemorrhage (0.9%), retroperitoneal bleeding, respiratory tract bleeding, anaphylaxis, angioedema, laryngeal edema, rash, urticaria, cholesterol embolism (clinical features may include livedo reticularis, "purple toe" syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, rhabdomyolysis), GU bleeding (<1% major), bleeding at catheter puncture site (<1% major)

Additional cardiovascular events associated with use in myocardial infarction: Cardiogenic shock, arrhythmias, AV block, pulmonary edema, heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial reinfarction, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, thrombosis, embolism, electromechanical dissociation, hypotension, fever, nausea, vomiting

Increased incidence of bleeding

Aminocaproic acid (antifibrinolytic agent) may decrease effectiveness.

Drugs which affect platelet function (eg, NSAIDs, dipyridamole, ticlopidine, clopidogrel, llb/llla antagonists) may potentiate the risk of hemorrhage; use with caution.

Heparin and aspirin: Use with aspirin and heparin may increase bleeding. However, aspirin and heparin were used concomitantly with tenecteplase in the majority of patients in clinical studies.

Warfarin or oral anticoagulants: Risk of bleeding may be increased during concurrent therapy.

Store at room temperature not to exceed 30°C (86°F) or under refrigeration 2°C to 8°C (36°F to 46°F). If reconstituted and not used immediately, store in refrigerator and use within 8 hours.

Initiates fibrinolysis by binding to fibrin and converting plasminogen to plasmin.

Distribution: V_d is weight related and approximates plasma volume

Metabolism: Primarily by the liver

Half-life: 90-130 minutes

Elimination: Cleared from the plasma at a rate of 99-119 mL/minute

I.V.:

If patient's weight:

<60 kg, dose: 30 mg

greater than or equal to 60 to <70 kg, dose: 35 mg

greater than or equal to 70 to <80 kg, dose: 40 mg

greater than or equal to 80 to <90 kg, dose: 45 mg

greater than or equal to 90 kg, dose: 50 mg

All patients received 150-325 mg of aspirin as soon as possible and then daily. Intravenous heparin was initiated as soon as possible and PTT was maintained between 50-70 seconds.

Dosage adjustment in renal impairment: No formal recommendations for renal impairment

Dosage adjustment in hepatic impairment: Severe hepatic failure is a relative contraindication. Recommendations were not made for mild to moderate hepatic impairment.

Elderly: Although dosage adjustments are not recommended, the elderly have a higher incidence of morbidity and mortality with the use of tenecteplase. The 30-day mortality in the ASSENT-2 trial was 2.5% for patients <65 years, 8.5% for patients 65-74 years, and 16.2% for patients greater than or equal to 75 years. The intracranial hemorrhage rate was 0.4% for patients <65, 1.6 % for patients 65-74 years, and 1.7 % for patients greater than or equal to 75. The risks and benefits of use should be weighted carefully in the elderly.

Tenecteplase should be reconstituted using the supplied 10 cc syringe with TwinPak™ dual cannula device and 10 mL sterile water for injection. Do not shake when reconstituting. Slight foaming is normal and will dissipate if left standing for several minutes. The reconstituted solution is 5 mg/mL. Any unused solution should be discarded. Tenecteplase is incompatible with dextrose solutions. Dextrose-containing lines must be flushed with a saline solution before and after administration. Administer as a single I.V. bolus over 5 seconds.

CBC, PTT, signs and symptoms of bleeding, EKG monitoring

This medication can only be administered I.V. You will have a tendency to bleed easily following its use; use caution to prevent injury (use electric razor, soft toothbrush), and use caution when using sharp objects (eg, scissors, knives). Strict bedrest should be maintained to reduce the risk of bleeding. If bleeding occurs, apply pressure to bleeding spot until bleeding stops completely. Report unusual bruising or bleeding; blood in urine, stool, or vomitus; bleeding gums; changes in vision; difficulty breathing; or chest pain/pressure.

Dextrose-containing lines must be flushed with a saline solution before and after administration. Check frequently for signs of bleeding. Avoid I.M. injections and nonessential handling of patient.

Powder for injection, lyophilized (recombinant): 50 mg

"Single-Bolus Tenecteplase Compared With Front-Loaded Alteplase in Acute Myocardial Infarction: The ASSENT-2 Double-blind Randomised Trial. Assessment of the Safety and Efficacy of a New Thrombolytic Investigators," Lancet, 1999, 354(9180):716-22.

Cannon CP, Gibson CM, McCabe CH, et al. "TNK-Tissue Plasminogen Activator Compared With Front-loaded Alteplase in Acute Myocardial Infarction. Results of the TIMI 10B Trial. Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators," Circulation, 1998, 98(25):2805-14.

Van de Werf F, Cannon CP, Luyten A, et al, "Safety Assessment of a Single-Bolus Administration of TNK Tissue-Plasminogen Activator in Acute Myocardial Infarction: The ASSENT-1 Trial. The ASSENT-1 Investigators," Am Heart J, 1999, 137(5):786-91.