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TNKase

Generic Name: Tenecteplase
Class: Thrombolytic Agents

Introduction

Thrombolytic agent; biosynthetic (recombinant DNA origin) form of human tissue-type plasminogen activator (t-PA).1 2 3 4 5 6 7

Uses for TNKase

Acute Myocardial Infarction

Management of acute MI in conjunction with anticoagulants (e.g., heparin) and/or platelet-aggregation inhibitors (e.g., aspirin); used to reduce post-MI mortality.1 5 7 10 15

30-day and 1-year mortality rates similar after tenecteplase 30–50 mg or an accelerated infusion of alteplase.1 5

Clinical benefit diminishes as the time period from symptom onset to initiation of therapy increases.10 15 Administer as soon as possible after onset of acute MI symptoms.1 AHA and ACC recommend administration within 30 minutes of hospital admission or first contact with the health-care system.10 15

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AHA and ACC recommend use of any marketed thrombolytic agent (e.g., tenecteplase, alteplase, reteplase) in patients having ischemic symptoms characteristic of MI for ≤12 hours and ST-segment elevation or new or presumed new left bundle-branch block.10 15

ACC and AHA state that thrombolytic therapy is reasonable within 12–24 hours of symptom onset in patients with persistent ischemic symptoms accompanied by ST-segment elevation, provided no contraindications exist.10 15

Thrombolytic therapy may be reasonable in patients with true posterior MI presenting within 12 hours after onset of symptoms, provided no contraindications exist.10

Pulmonary Embolism

Has been used for the treatment of acute PE.16 17 20 1005

The American College of Chest Physicians (ACCP) generally recommends against the use of systemic thrombolytic therapy in most patients with acute PE; however, in patients with acute PE associated with hypotension (e.g., systolic BP <90 mm Hg), thrombolytic therapy may provide some benefit in terms of mortality reduction and is suggested as a possible treatment in patients without a high risk of bleeding.1005

TNKase Dosage and Administration

General

  • Initiate therapy as soon as possible after acute MI.1 9 10 15 (See Acute Myocardial Infarction under Uses.)

Administration

IV Administration

For solution compatibility information, see Solution Compatibility under Stability.

Administer IV.1

Reconstitution

Consult the manufacturer's labeling for instructions for using the B-D 10-mL Syringe with TwinPak Dual Cannula Device for reconstitution and administration.1

Reconstitute with 10 mL of sterile water for injection without preservatives to provide a solution containing 5 mg/mL.1

If foaming (usually slight) occurs, leave vial undisturbed for several minutes to allow dissipation of any large bubbles.1 Gently swirl until contents are completely dissolved; avoid shaking.1

Rate of Administration

Administer over 5 seconds.1

Dosage

Expressed in mg.1

Biologic potency is determined using an in vitro clot lysis assay and is expressed in tenecteplase-specific units.1 Each mg is equivalent to 200 tenecteplase-specific units.1

Dose based on patient weight.1 9

Adults

Acute MI
IV

Patient Weight (kg)

Tenecteplase Dose (mg)

<60

30

≥60 to <70

35

≥70 to <80

40

≥80 to <90

45

≥90

50

Prescribing Limits

Adults

Acute MI
IV

Total dose should not exceed 50 mg.1 9

Cautions for TNKase

Contraindications

  • Active internal bleeding.1 10 15

  • History of cerebrovascular accident.1 10

  • Recent (within 2 months) intracranial or intraspinal surgery or trauma.1 10

  • Intracranial neoplasm.1 10 15

  • Intracranial vascular disease (i.e., arteriovenous malformation, aneurysm).1 10 15

  • Known bleeding diathesis.1 10 15

  • Severe uncontrolled hypertension.1 10

  • History of intracranial hemorrhage.10 15

  • Suspected aortic dissection.10 15

  • Recent (within 3 months) closed-head or facial trauma.10 15

Warnings/Precautions

Warnings

Effects on Hemostasis

Possible bleeding involving internal bleeding at intracranial or retroperitoneal sites or bleeding from the GI, GU, or respiratory tract.1 Superficial or surface bleeding at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or sites of recent surgical intervention also may occur.1

Weigh increased risks of therapy against anticipated benefits in patients with recent major surgery (e.g., CABG), obstetric delivery, organ biopsy, previous puncture of noncompressible vessels, cerebrovascular disease, hypertension (SBP ≥180 mm Hg and/or DBP ≥110 mm Hg), hemostatic defects (e.g., secondary to severe hepatic or renal disease), recent GI (active peptic ulcer) or GU bleeding, or recent trauma.1 10 Also, weigh risks against benefits of therapy in patients with diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions.1 Weigh risks against benefits in patients receiving concurrent oral anticoagulant therapy (e.g., warfarin) or recent therapy with platelet glycoprotein (GP IIb/IIIa) inhibitors.1 10 Weigh risks against benefits in patients with any condition in which bleeding constitutes a substantial hazard or would be particularly difficult to manage because of its location.1

Initiate therapy only after careful screening for contraindications.1

Minimize risk of bleeding by carefully selecting patients and monitoring all potential bleeding sites (e.g., venous punctures).1 Avoid IM injections for the first few hours following therapy.1 Perform invasive venous procedures carefully and as infrequently as possible.1 Minimize arterial punctures.1 Avoid arterial and venous invasive procedures in areas that are inaccessible to manual compression (e.g., internal jugular or subclavian punctures).1 Use of an artery in an upper extremity is preferred if an arterial puncture is essential.1 Apply pressure to the puncture site for ≥30 minutes followed by a pressure dressing and frequent inspection of the puncture site for bleeding.1

If serious bleeding occurs, immediately discontinue heparin and platelet-aggregation inhibitors.1 Can reverse heparin anticoagulation with protamine sulfate.1

Cardiovascular Effects

Weigh risks against anticipated benefits of therapy in patients with a high likelihood of left heart thrombus (e.g., mitral stenosis with atrial fibrillation), acute pericarditis, subacute bacterial endocarditis, septic thrombophlebitis, or an occluded arteriovenous cannula at a seriously infected site.1

Cholesterol Embolization

Possibly fatal cholesterol crystal embolization associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or thrombolytic agents.1 Clinical features of cholesterol embolism include livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, MI, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.1

Arrhythmias

Possible reperfusion-related arrhythmias (e.g., sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia).1

Manage with standard antiarrhythmic measures.1 Have appropriate antiarrhythmic therapy available during and after administration.1

Sensitivity Reactions

Hypersensitivity Reactions

Allergic-type reactions (e.g., angioedema, laryngeal edema, rash, urticaria) or anaphylactoid reactions reported rarely.1

Institute appropriate therapy if an anaphylactoid reaction occurs.1

Readministration

Use with caution in patients with previous drug exposure.1 8 Repeat courses not systematically studied.1

Specific Populations

Pregnancy

Category C.1

Increased risk of therapy in pregnant women; weigh risks against benefits of therapy in pregnant women.1

Lactation

Not known whether tenecteplase is distributed into milk.1 Caution if used in nursing women.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 8

Geriatric Use

Intracranial hemorrhage, stroke, death, and major bleeding (i.e., bleeding requiring blood transfusions or leading to hemodynamic compromise) more frequent in patients ≥65 years of age than in younger adults.1 Weigh risks of drug against potential benefits.1

Hepatic Impairment

Weigh risks of therapy against potential benefits in patients with severe hepatic impairment.1

Common Adverse Effects

Bleeding.1

Interactions for TNKase

Specific Drugs

Drug

Interaction

Comments

Aspirin

Increased risk of hemorrhage1 10

Dipyridamole

Increased risk of hemorrhage1 10

Safety of concomitant therapy not established1

GP IIb/IIIa-receptor inhibitors

Increased risk of hemorrhage1 10

Safety of concomitant therapy not established1

Weigh risks against benefits1

Heparin

Increased risk of hemorrhage1 10

Warfarin

Increased risk of hemorrhage1 10

Weigh risks against benefits1

TNKase Pharmacokinetics

Distribution

Extent

Not known whether tenecteplase is distributed into human milk.1

Elimination

Metabolism

Cleared by the liver.1 21

Half-life

Initial half-life is 20–24 minutes.1 21 22 Terminal half-life is 90–130 minutes.1 3 21

Stability

Storage

Parenteral

Powder for Injection

Controlled room temperature ≤30°C or under refrigeration at 2–8°C.1

Reconstituted solutions contain no preservative.1 Preferably use solution immediately after preparation; may be used up to 8 hours after reconstitution if refrigerated.1 Discard any unused solution after 8 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Incompatible with dextrose.1

If administered via an IV administration set that is used for infusing a dextrose-containing solution, flush line with 0.9% sodium chloride-containing solution prior to and following drug administration.1

Do not use bacteriostatic water for injection as diluent.1

Actions

  • Binds to fibrin and converts plasminogen to plasmin.1

  • A relatively fibrin-selective plasminogen activator.1 Exhibits higher fibrin selectivity and greater resistance to plasminogen-activator inhibitors (e.g., PAI-1) than alteplase.2 3 4 5 6 7

Advice to Patients

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses or recent surgery.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Tenecteplase

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For IV use only

50 mg (with sterile water for injection)

TNKase

Genentech

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 11, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Genentech. TNKase (tenecteplase) injection prescribing information. South San Francisco, CA; 2006 Apr.

2. Van de Werf F. What do new lytics add to t-PA?Am Heart J. 1999; 138:S115- 20.

3. Verstraete M. Third-generation thrombolytic drugs. Am J Med. 2000; 109:52-8. [IDIS 451352] [PubMed 10936478]

4. Van de Werf F, Cannon CP, Luyten A et al for the ASSENT-1 investigators. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. Am Heart J. 1999; 137:786-91. [PubMed 10220625]

5. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999; 354:716-22. [PubMed 10475182]

6. Cannon CP, McCabe CH, Gibson CM et al and the TIMI 10A Investigators TNK-tissue plasminogen activator in acute myocardial infarction: results of the Thrombolysis in Myocardial Infraction (TIMI) 10A Dose-Ranging Trial. Circulation. 1997; 95:351-6.

7. Cannon CP, Gibson CM, McCabe CH et al for the Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B Trial. Circulation. 1998; 98:2805-14. [IDIS 450788] [PubMed 9860780]

8. Genentech, Inc., South San Francisco, CA: Personal communication.

9. The American Heart Association in Collaboration with the International Liaison Committee on Resuscitation. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2000; 102(Suppl I) 172-203.

10. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). 2004. From website.

13. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1999; 34:89-911.

15. The American Heart Association. Guidelines 2005 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005; 112(Suppl I):IV1-211.

16. Becattini C, Agnelli G, Salvi A et al. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res. 2010; 125:e82-6. [PubMed 19833379]

17. Steering Committee. Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial. Am Heart J. 2012; 163:33-38.e1. [PubMed 22172434]

20. Konstantinides S. Clinical practice. Acute pulmonary embolism. N Engl J Med. 2008; 359:2804-13. [PubMed 19109575]

21. Tanswell P, Modi N, Combs D et al. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet. 2002; 41:1229-45. [PubMed 12452736]

22. Modi NB, Fox NL, Clow FW et al. Pharmacokinetics and pharmacodynamics of tenecteplase: results from a phase II study in patients with acute myocardial infarction. J Clin Pharmacol. 2000; 40:508-15. [PubMed 10806604]

1005. Kearon C, Akl EA, Comerota AJ et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e419S-94S. [PubMed 22315268]

1013. Monagle P, Chan AK, Goldenberg NA et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e737S-801S. [PubMed 22315277]

1016. Eikelboom JW, Hirsh J, Spencer FA et al. Antiplatelet drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e89S-119S.

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