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Medication Safety Issues
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication (I.V.) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(RE ta plase)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of ST-elevation myocardial infarction (STEMI); improvement of ventricular function; reduction of the incidence of CHF and the reduction of mortality following AMI
Recommended criteria for treatment: STEMI: Chest pain ?20 minutes duration, onset of chest pain within 12 hours of treatment (or within prior 12-24 hours in patients with continuing ischemic symptoms), and ST-segment elevation >0.1 mV in at least two contiguous precordial leads or two adjacent limb leads on ECG or new or presumably new left bundle branch block (LBBB)
Pregnancy Risk Factor
C
Lactation
Excretion in breast milk unknown/use caution
Contraindications
Hypersensitivity to reteplase or any component of the formulation; active internal bleeding; history of cerebrovascular accident; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm, arteriovenous malformations, or aneurysm; known bleeding diathesis; severe uncontrolled hypertension
Warnings/Precautions
Concerns related to adverse effects:
• Anaphylaxis: Rare anaphylactic reactions can occur.
• Arrhythmias: Coronary thrombolysis may result in reperfusion arrhythmias.
• Bleeding: Monitor all potential bleeding sites. If serious bleeding occurs, the infusion of reteplase and heparin should be stopped.
• Cholesterol embolism: Has rarely been reported.
Disease-related concerns:
• Conditions that increase bleeding risk: For the following conditions the risk of bleeding is higher with use of reteplase and should be weighed against the benefits of therapy: recent (within 10 days) major surgery (eg, CABG, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels), cerebrovascular disease, recent gastrointestinal or genitourinary bleeding, recent trauma including CPR, hypertension (systolic BP >180 mm Hg and/or diastolic BP >110 mm Hg), high likelihood of left heart thrombus (eg, mitral stenosis with atrial fibrillation), acute pericarditis, subacute bacterial endocarditis, hemostatic defects including ones caused by severe renal or hepatic dysfunction, significant hepatic dysfunction, diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, septic thrombophlebitis or occluded AV cannula at seriously infected site, or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of location.
• Myocardial infarct (MI): Appropriate use: Follow standard management for MI while infusing reteplase.
Concurrent drug therapy issues:
• Anticoagulants: Use with caution in patients receiving oral anticoagulants; increased risk of bleeding.
• Heparin: Concurrent heparin anticoagulation may contribute to bleeding.
Special populations:
• Elderly: Use with caution in patients with advanced age (eg, >75 years); increased risk of bleeding.
• Pediatrics: Safety and efficacy have not been established in children.
• Pregnancy: Use with caution in pregnancy; increased risk of bleeding.
Other warnings/precautions:
• Administration: Intramuscular injections and nonessential handling of the patient should be avoided. Venipunctures should be performed carefully and only when necessary. If arterial puncture is necessary, use an upper extremity vessel that can be manually compressed.
Adverse Reactions
Bleeding is the most frequent adverse effect associated with reteplase. Heparin and aspirin have been administered concurrently with reteplase in clinical trials. The incidence of adverse events is a reflection of these combined therapies, and are comparable with comparison thrombolytics.
>10%: Local: Injection site bleeding (4.6% to 48.6%)
1% to 10%:
Gastrointestinal: Bleeding (1.8% to 9.0%)
Genitourinary: Bleeding (0.9% to 9.5%)
Hematologic: Anemia (0.9% to 2.6%)
<1% (Limited to important or life-threatening): Intracranial hemorrhage (0.8%), allergic/anaphylactoid reactions, cholesterol embolization
Other adverse effects noted are frequently associated with MI (and therefore may or may not be attributable to Retavase®) and include arrhythmia, hypotension, cardiogenic shock, pulmonary edema, cardiac arrest, reinfarction, pericarditis, tamponade, thrombosis, and embolism.
Drug Interactions
Anticoagulants: Thrombolytic Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Aprotinin: May diminish the therapeutic effect of Thrombolytic Agents. Risk D: Consider therapy modification
Drotrecogin Alfa: Thrombolytic Agents may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Risk D: Consider therapy modification
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Thrombolytic Agents. Bleeding may occur. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy
Salicylates: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy
Storage
Dosage kits should be stored at 2°C to 25°C (36°F to 77°F) and remain sealed until use in order to protect from light.
Reconstitution
Reteplase should be reconstituted using the diluent, syringe, needle, and dispensing pin provided with each kit.
Mechanism of Action
Reteplase is a nonglycosylated form of tPA produced by recombinant DNA technology using E. coli; it initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converts entrapped plasminogen to plasmin
Pharmacodynamics/Kinetics
Onset of action: Thrombolysis: 30-90 minutes
Half-life elimination: 13-16 minutes
Excretion: Feces and urine
Clearance: Plasma: 250-450 mL/minute
Dosage
Children: Not recommended
Adults: 10 units I.V. over 2 minutes, followed by a second dose 30 minutes later of 10 units I.V. over 2 minutes; withhold second dose if serious bleeding or anaphylaxis occurs
Note: All patients should receive 162-325 mg of chewable nonenteric coated aspirin as soon as possible and then daily. Administer concurrently with heparin 60 units/kg bolus (maximum: 4000 units) followed by continuous infusion of 12 units/kg/hour (maximum: 1000 units/hour) and adjust to aPTT target of 50-70 seconds (or 1.5-2 times the upper limit of control).
Administration: I.V.
Infuse over 2 minutes.
Administration: I.V. Detail
No other medications should be added to the injection solution.
Monitoring Parameters
Monitor for signs of bleeding (hematuria, GI bleeding, gingival bleeding)
Patient Education
This medication can only be administered by infusion; you will be monitored closely during and after treatment. You will have a tendency to bleed easily; use caution to prevent injury (use electric razor, soft toothbrush, and caution with knives, needles, or anything sharp). Follow instructions for strict bedrest to reduce the risk of injury. If bleeding occurs, report immediately and apply pressure to bleeding spot until bleeding stops completely. Report unusual pain (acute headache, joint pain, chest pain); unusual bruising or bleeding; blood in urine, stool, or vomitus; bleeding gums; vision changes; or respiratory difficulty. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.
Geriatric Considerations
No specific changes in use in the elderly are necessary.
Anesthesia and Critical Care Concerns/Other Considerations
Evidence-Based Information:
Management of Intracerebral Hemorrhage (ICH) Due to Thrombolysis: Overall management of ICH is similar regardless of cause; however, iatrogenic spontaneous ICH may have specific treatments. According to the 2007 ACC/ASA Guidelines for the Management of Spontaneous Intracerebral Hemorrhage, fibrinolytic-related ICH should be treated with infusion of platelets (6-8 units) and cryoprecipitate which contains factor VIII (Class IIb recommendation).
Cardiovascular Considerations
ST-Elevation Myocardial Infarction (STEMI): The 2004 ACC/AHA guidelines for the management of patients with acute myocardial infarction recommend prehospital thrombolysis in special circumstances (eg, transport time >30 minutes). Efforts to quickly identify and safely treat appropriate candidates for therapy continue. Reducing treatment delays is very important to improve mortality. Thrombolytic therapy is indicated in patients with ST-segment elevation of >1 mm in two or more contiguous leads or at least 2 adjacent limb leads in patients with chest discomfort >30 minutes but ?12 hours. Patients with chest discomfort suggestive of ischemia and new-onset left bundle branch block (LBBB) are also candidates for thrombolysis. Generally there is only a small trend for benefit of therapy after a delay of more than 12-24 hours, but thrombolysis may be considered for selected patients with ongoing ischemic pain and extensive ST elevation. Additional absolute contraindications for fibrinolysis use in ST-elevation myocardial infarction from the 2004 ACC/AHA guidelines: Any prior intracranial hemorrhage, ischemic stroke within 3 months (except one within 3 hours), significant closed head or facial trauma within 3 months. Additional relative contraindications include history of chronic severe, poorly-controlled hypertension, severe uncontrolled hypertension on presentation (systolic BP >180 mm Hg or diastolic >110 mm Hg; could be an absolute contraindication in low-risk patients), history of prior ischemic stroke > 3 months, dementia, or known intracranial pathology, traumatic or prolonged (>10 minutes) CPR or major surgery (<3 weeks), recent (within 2-4 weeks) internal bleeding, noncompressible vascular punctures, pregnancy, active peptic ulcer, current use of anticoagulants.
Thrombolytic and GP IIb/IIIa Inhibitor: In the GUSTO V trial, patients with acute MI were randomized to standard-dose reteplase or half-dose reteplase (two boluses of 5 units each, 30 minutes apart) and full dose abciximab. Thirty-day mortality (primary endpoint) was similar in both groups. The combination treatment group had fewer deaths or nonfatal reinfarctions, less need for urgent revascularization, fewer major ischemic complications. More bleeding occurred in the combination treatment group, but intracranial hemorrhage and nonfatal disabling stroke were similar in both groups. All cause mortality at one year was similar in both groups. In TIMI 14, the combination of full-dose abciximab (0.25 mg/kg bolus followed by a 12-hour infusion of 0.125 mcg/kg/minute, maximum 10 mcg/minute) and half-dose alteplase (15 mg bolus followed by 35 mg infusion over 60 minutes) resulted in 74% of patients achieving TIMI grade 3 flow at 90 minutes. The 2004 ACC/AHA guidelines for the management of patients with acute myocardial infarction suggests that abciximab and half-dose reteplase or tenecteplase may be considered for prevention of reinfarction in patients with an anterior MI, who <75 years of age and have no risk factors for bleeding.
However, more recently, the 2008 American College of Chest Physicians guidelines recommends against the combination of half-dose reteplase or tenecteplase and standard-dose abciximab (with low dose unfractionated heparin) in any patient with STEMI due to the lack of mortality benefit and the risk of major bleeding (Goodman, 2008).
Facilitated Percutaneous Coronary Intervention (PCI): Facilitated PCI describes administration of a thrombolytic, a glycoprotein (GP) IIb/IIIa inhibitor, or a combination of the two in addition to standard treatment prior to planned PCI for STEMI. The concept is based on the premise that the patient will have a higher likelihood of entering the procedure with an open-artery which has been shown to improve outcomes at least in patients who have spontaneous reperfusion. Although a number of facilitated PCI clinical trials have shown that a higher rate of patients enter the catheterization laboratory with an open coronary artery, clinical outcomes are not improved, safety is compromised (eg, increased rates of bleeding complications), and mortality may be increased (Keeley, 2006). More recently, the FINESSE trial (Ellis, 2008), a prospective, international, multicenter trial, enrolled 2452 high-risk patients with STEMI and randomized them to either facilitated PCI with half-dose reteplase and abciximab, facilitated PCI with abciximab alone, or primary PCI with abciximab administered at the time of PCI. The primary endpoint of the trial was a composite of all-cause mortality and post-MI complications (ventricular fibrillation occurring >48 hours after randomization, cardiogenic shock, and CHF requiring hospitalization or emergency department visit within 90 days). Although patients who received a facilitated strategy with reteplase/abciximab had higher rates of ST-segment resolution at 60-90 minutes and TIMI 3 flow prior to PCI compared to facilitated PCI with abciximab or primary PCI with abciximab, there was no difference in the primary endpoint or 90-day mortality among the groups. Facilitated PCI significantly increased the incidence of nonintracranial TIMI major and minor bleeding. Of note, 5 patients in the reteplase/abciximab group developed an intracranial hemorrhage. The authors concluded that there is no clinical benefit in facilitating PCI with abciximab or half-dose reteplase/abciximab. If PCI is the chosen strategy for reperfusion, patients should be given a GPIIb/IIIa inhibitor at the time of PCI. Currently, the ACC/AHA/SCAI 2007 Update for PCI and the ACC/AHA 2007 Update for STEMI recommend facilitated PCI with agents other than full-dose thrombolytics in patients who are high-risk (eg, large MI, hemodynamic or electrical instability), low risk of bleeding, and when PCI is not immediately available within 90 minutes. The 2008 Chest guidelines do not recommend facilitated PCI with a thrombolytic (with or without GP IIb/IIIa inhibition) in any patient with STEMI.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Bleeding is the most frequent adverse effect of reteplase. See Effects on Bleeding.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Use caution when there is significant risk of bleeding (see Warnings/Precautions for specific use cautions). Assess potential risk interactions with other pharmacological and herbal products patient may be taking (especially those medications that may affect coagulation or platelet function). See Administration for infusion specifics. Patient should be closely monitored for bleeding during and following treatment: infusion site, neurological status (eg, intracranial hemorrhage), vital signs, and ECG. Bleeding precautions should be maintained; avoid I.M. injections, venipunctures (unless absolutely necessary), and nonessential handling of the patient. If arterial puncture is necessary, use an upper extremity vessel that can be manually compressed. Patient instructions determined by patient condition.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution [preservative free]:
Retavase®: 10.4 units [equivalent to reteplase 18.1 mg; contains sucrose and polysorbate 80; packaged with sterile water for injection]
References
“A Comparison of Reteplase With Alteplase for Acute Myocardial Infarction. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators,” N Engl J Med, 1997, 337(16):1118-23.
Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed October 26, 2004.
Antman EM, Hand M, Armstrong PW, et al, “2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2008, 51(2):210-49.
Broderick J, Connolly S, Feldmann E, et al, "Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults: 2007 Update: A Guideline From the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group," Stroke, 2007, 38(6):2001-23. Available at http://stroke.ahajournals.org/cgi/content/short/STROKEAHA.107.183689.
Ellis SG, Tendera M, de Belder MA, et al, “Facilitated PCI in Patients With ST-Elevation Myocardial Infarction,” N Engl J Med, 2008, 358(21):2205-17.
Goodman SG, Menon V, Cannon CP, et al, “Acute ST-Segment Elevation Myocardial Infarction: American College of Chest Physicians Evidence-Based Clinical Practice,” Chest, 2008, 133(6 Suppl):708-75.
King SB 3rd, Smith SC Jr, Hirshfeld JW Jr, et al, “2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2008, 51(2):172-209.
Lincoff AM, Califf RM, Van de Werf F, et al, “Mortality at 1 Year With Combination Platelet Glycoprotein IIb/IIIa Inhibition and Reduced-Dose Fibrinolytic Therapy vs Conventional Fibrinolytic Therapy for Acute Myocardial Infarction: GUSTO V Randomized Trial,” JAMA, 2002, 288(17):2130-5.
Ryan TJ, Anderson JK, Antman EM, et al, “ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction: 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, 1996, 28:1328-428.
Smalling RW, Bode C, Kalbfleisch J, et al, “More Rapid, Complete, and Stable Coronary Thrombolysis With Bolus Administration of Reteplase Compared With Alteplase Infusion in Acute Myocardial Infarction. RAPID Investigators,” Circulation, 1995, 91(11):2725-32.
Topol EJ, GUSTO V Investigators, “Reperfusion Therapy for Acute Myocardial Infarction With Fibrinolytic Therapy or Combination Reduced Fibrinolytic Therapy and Platelet Glycoprotein IIb/IIIa Inhibition: The GUSTO V Randomized Trial,” Lancet, 2001, 357:1905-14.
International Brand Names
Lexi-Comp.com
Last full review/revision December 2009
Content last modified December 2009
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