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Reteplase

Class: Thrombolytic Agents
Chemical Name: 173-l-Serine-174-l-lysine-175-l-glutamine-173-527-plasminogen activator (human tissue-type)
Molecular Formula: C1736H2653N499O522S22
CAS Number: 133652-38-7
Brands: Retavase

Introduction

Thrombolytic agent; biosynthetic (recombinant DNA origin) form of human tissue-type plasminogen activator (t-PA).1

Uses for Reteplase

Acute MI

Management of selected cases of acute evolving transmural MI in conjunction with anticoagulants (e.g., heparin) and/or platelet-aggregation inhibitors (i.e., aspirin).1 2 3 7 15 Used to improve ventricular function and reduce the incidence of CHF, cardiogenic shock, and associated post-MI mortality.1 2 3 7 8

Clinical benefit diminishes as the time period from symptom onset to initiation of therapy increases.2 3 5 6 15 19 Administer as soon as possible, preferably within 3–6 hours of acute MI.1 3 5 6 19 ACC and AHA recommend administration within 30 minutes of hospital admission or first contact with the health-care system.15 19

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AHA and ACC recommend use of any marketed thrombolytic agent (e.g., alteplase, reteplase, tenecteplase) in patients having ischemic symptoms characteristic of MI for ≤12 hours and ST-segment elevation or new or presumed new left bundle-branch block, unless contraindications exist.15 19

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.15 19

Thrombolytic therapy may be reasonable in patients with true posterior MI presenting within 12 hours after onset of symptoms.15 19

Acute PE

Has been used for the treatment of acute PE.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 mmHg), thrombolytic therapy may provide some benefit in terms of mortality reduction and is suggested as a possible treatment in patients without high risk of bleeding.1005

Reteplase Dosage and Administration

General

  • Institute therapy as soon as possible after acute MI.1 3 5 6 15 (See Acute MI under Uses.)

Administration

IV Administration

For drug compatibility information, see Drug Compatibility under Stability.

Administer IV.1

Do not add other IV substances, additives, or other drugs to reteplase solution and do not infuse anything else simultaneously through the same IV line.1

If administered via an IV administration set that is used for infusing heparin, flush line with 0.9% sodium chloride or 5% dextrose solution prior to and following drug administration.1

Reconstitution

Reconstitute with 10 mL of sterile water for injection without preservatives to provide a solution containing 1 unit/mL.1 Use dispensing pin and diluent provided by the manufacturer.1 12

If foaming (usually slight) occurs, leave the vial undisturbed for several minutes.1 Gently swirl until the contents are completely dissolved; avoid shaking.1

Rate of Administration

Administer over 2 minutes.1

Dosage

Expressed in reteplase-specific units, but also may be expressed in mg; each reteplase-specific unit is equivalent to 1.74 mg.1

Adults

Acute MI
IV

Total dose is 20 units, given as two 10-unit IV injections 30 minutes apart.1

Lower doses of reteplase (two 5-unit doses 30 minutes apart) have been used in conjunction with a platelet glycoprotein (GP IIb/IIIa)-receptor inhibitor, heparin, and aspirin.13 14 15 (See Interactions.)

Cautions for Reteplase

Contraindications

  • Active internal bleeding.1 3 9 15 19

  • History of cerebrovascular accident.1 8 15

  • Recent intracranial or intraspinal surgery or trauma.1 9 15

  • Intracranial neoplasm.1 7 15 19

  • Intracranial vascular disease (i.e., arteriovenous malformation, aneurysm).1 7 15 19

  • Known bleeding diathesis.1 7 15 19

  • Severe uncontrolled hypertension.1 6 7 9 11 15

  • History of intracranial hemorrhage.15 19

  • Suspected aortic dissection.15 19

  • Recent (within 3 months) facial trauma.15 19

Warnings/Precautions

Warnings

Effects on Hemostasis

Possible bleeding, including 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 (e.g., active peptic ulcer) or GU bleeding, or recent trauma.1 15 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).1 15 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., sites of all venous cutdowns, arterial and venous punctures, needle punctures).1 Avoid IM injections and nonessential handling of patient.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 anticoagulant therapy; heparin anticoagulation can be reversed with protamine sulfate.1 Do not administer a second injection of reteplase if serious bleeding occurs with the first injection.1

Cardiovascular Effects

Possible fatal cardiogenic shock, heart failure, cardiac arrest, recurrent myocardial ischemia or infarction, myocardial rupture, AV block, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, hypotension, pulmonary edema, or thromboembolism.1

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, acute renal failure, gangrenous digits/purple toe syndrome, 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, VPCs, VT).1 6 10 11

Have appropriate antiarrhythmic therapy available during and after administration.1 6

Sensitivity Reactions

Sensitivity Reactions

Allergic-type (e.g., pruritus, rash, urticaria) or anaphylactoid reactions (e.g., dyspnea, hypotension) reported rarely.1 7 13

Institute appropriate therapy if an anaphylactoid reaction occurs.1

Readministration

Repeat courses not systematically studied.1 Do not administer second dose if anaphylaxis occurs with first dose.1

Specific Populations

Pregnancy

Category C.1

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

Lactation

Not known whether reteplase 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 13

Geriatric Use

Intracranial hemorrhage more common.1 5 6 Weigh risks of drug against potential benefits.1

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

Bleeding.1

Interactions for Reteplase

Specific Drugs

Drug

Interaction

Comments

Abciximab

Increased risk of hemorrhage1 14 15

Aspirin

Increased risk of hemorrhage1 14 15

Monitor carefully for bleeding, especially at arterial puncture sites1

Dipyridamole

Increased risk of hemorrhage1 14 15

Heparin

Increased risk of hemorrhage1 14 15

Monitor carefully for bleeding, especially at arterial puncture sites1

Warfarin

Increased risk of hemorrhage1 15

Weigh risks against anticipated benefits1

Reteplase Pharmacokinetics

Distribution

Extent

Not known whether reteplase is distributed into human milk.1

Elimination

Metabolism

Cleared by the liver and kidney.1

Half-life

13–16 minutes.1

Stability

Storage

Parenteral

Powder for Injection

2–25°C; protect from light.1

Reconstituted solutions contain no preservative.1 Preferably use solution immediately after preparation; may be used up to 4 hours after reconstitution if stored at 2–30°C.1 Discard any unused solution after 4 hours.1

Compatibility

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

Parenteral

Drug Compatibility

Reteplase is incompatible with heparin.1

Y-Site CompatibilityHID

Incompatible

Bivalirudin

Actions

  • Binds to fibrin and converts plasminogen to plasmin.1 Plasmin degrades the fibrin matrix of the thrombus.1

  • Decreased fibrin affinity compared with alteplase.2 3 7 8 10

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 6

  • 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.

Reteplase

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For IV use only

10.4 units (18.1 mg)

Retavase (with reconstitution kit containing sterile water for injection diluent and a double-ended sterile dispensing pin)

PDL BioPharma

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 14, 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. PDL BioPharma, Inc. Retavase (reteplase, recombinant) injection prescribing information. Freemont, CA; 2006 Jan.

2. Topol EJ, Ohman M, Armstrong PW et al. Survival outcomes 1 year after reperfusion therapy with either alteplase or reteplase for acute myocardial infarction: results from the Global utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) III trial. Circulation. 2000; 102:1761-5. [IDIS 454027] [PubMed 11023929]

3. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med. 1997; 337:118-23.

5. 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.

6. Internation Liason Committee on Resuscitation. Guidelines 2000 for cardiopulmonary rsuscitation and emergency cardiovascular care: an international consensus on science. Part 7, section 1. Acute coronary syndromes (acute myocardial infarction). Circulation. 2000; 102(Suppl. I):I-172-203.

7. International Joint Efficacy Comparison of Thrombolytics. Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet. 1995; 346:329-36. [IDIS 351255] [PubMed 7623530]

8. Smalling RW, Bode C, Kalbfleisch J et al et al. More rapid, complete, and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction. Circulation. 1995; 91:2725-32. [IDIS 348924] [PubMed 7758177]

9. Bode C, Smalling RW, Berg G et al et al. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. Circulation. 1996; 94:891-8. [IDIS 372165] [PubMed 8790022]

10. Tebbe U, von Essen R, Smolarz A et al. Open, noncontrolled dose-finding study with a novel recombinant plasminogen activator (BM 06.022) given as a double bolus in patients with acute myocardial infarction. Am J Cardiol. 1993; 72:518-24. [IDIS 319465] [PubMed 8362764]

11. Neuhaus KL, von Essen R, Vogt A et al. Dose finding with a novel recombinant plasminogen activator (BM 06.022) in patients with acute myocardial infarction: results of the German recombinant plasminogen activator study. J Am Coll Cardiol. 1994; 24:55-60. [IDIS 332009] [PubMed 8006283]

12. Boehringer Mannheim Corporation, Gaithersburg, MD: Personal communication.

13. Centocor Inc., Malvern, PA: Personal communication.

14. Topol EJ, GUSTO V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combinaiton reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomized trial. Lancet. 2001; 357: 1905-14.

15. 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.

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

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

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]

HID. Trissel LA. Handbook on injectable drugs. 14th ed; Bethesda, MD: American Society of Health-System Pharmacists; 2007:1462.

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