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Retavase

Generic Name: 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

Introduction

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

Uses for Retavase

Acute MI

Used for reperfusion therapy in patients with acute MI, in conjunction with appropriate anticoagulant (e.g., heparin) and antiplatelet (e.g., aspirin and clopidogrel) therapies.1 2 3 7 527

Current standard of care in patients with ST-segment-elevation MI (STEMI) is timely reperfusion (with primary PCI or thrombolytic therapy).527 994 The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline states that reperfusion therapy should be administered to all eligible patients with STEMI and onset of ischemic symptoms within the previous 12 hours.527 994 Select the appropriate reperfusion method based on a risk-benefit analysis, considering the time from onset of MI symptoms, patient's clinical and hemodynamic status, comorbidities (e.g., severe heart failure), bleeding risk, contraindications, and availability (and timeliness) of PCI.527

Primary PCI is preferred when it can be performed in a timely manner.527 994 Thrombolytic therapy is recommended when it is anticipated that PCI cannot be performed within 120 minutes of first medical contact.527

Benefits of thrombolytic therapy in patients with STEMI are well established;527 resulting reperfusion with reteplase shown to improve ventricular function and reduce incidence of heart failure, cardiogenic shock, and death.1 2 7 8

Clinical benefit diminishes as the time period from symptom onset to initiation of therapy increases; administer as soon as possible after onset of MI symptoms.1 3 527 ACCF and AHA recommend administration within 30 minutes of hospital arrival.527

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

Retavase Dosage and Administration

General

  • Institute therapy as soon as possible after acute MI.1 3 527 (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 (See Interactions.)

Cautions for Retavase

Contraindications

  • Active internal bleeding.1 3 9

  • History of cerebrovascular accident.1 8

  • Recent intracranial or intraspinal surgery or trauma.1 9

  • Intracranial neoplasm.1 7

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

  • Known bleeding diathesis.1 7

  • Severe uncontrolled hypertension.1 7 9 11

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 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 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 10 11

Have appropriate antiarrhythmic therapy available during and after administration.1

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 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 Retavase

Specific Drugs

Drug

Interaction

Comments

Abciximab

Increased risk of hemorrhage1 14

Aspirin

Increased risk of hemorrhage1 14

Monitor carefully for bleeding, especially at arterial puncture sites1

Dipyridamole

Increased risk of hemorrhage1 14

Heparin

Increased risk of hemorrhage1 14

Monitor carefully for bleeding, especially at arterial puncture sites1

Warfarin

Increased risk of hemorrhage1

Weigh risks against anticipated benefits1

Retavase 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

  • 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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 sterile dispensing pin)

EKR Therapeutics

AHFS DI Essentials. © Copyright 2017, Selected Revisions October 23, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, 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. [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.

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. [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. [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. [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. [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. [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.

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

527. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013; 127:e362-425. [PubMed 23247304]

803. Lamas GA, Escolar E, Faxon DP. Examining treatment of ST-elevation myocardial infarction: the importance of early intervention. J Cardiovasc Pharmacol Ther. 2010; 15:6-16. [PubMed 20061507]

805. Reed GW, Rossi JE, Cannon CP. Acute myocardial infarction. Lancet. 2017; 389:197-210. [PubMed 27502078]

807. Smith JN, Negrelli JM, Manek MB et al. Diagnosis and management of acute coronary syndrome: an evidence-based update. J Am Board Fam Med. 2015 Mar-Apr; 28:283-93. [PubMed 25748771]

994. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011; 58:e44-122. [PubMed 22070834]

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]

1100. Amsterdam EA, Wenger NK, Brindis RG et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 130:e344-426. [PubMed 25249585]

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

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