Reteplase

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Reteplase
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

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Overview

Reteplase is a tissue plasminogen activator that is FDA approved for the {{{indicationType}}} of acute myocardial infarction. Common adverse reactions include bleeding.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Acute Myocardial Infarction
  • Reteplase is indicated for use in the management of acute myocardial infarction (AMI) in adults for the improvement of ventricular function following AMI, the reduction of the incidence of congestive heart failure and the reduction of mortality associated with AMI.
  • Treatment should be initiated as soon as possible after the onset of AMI symptoms
  • Dosing Information
  • First dose: 10 unit IV bolus over 2 minutes
  • Second dose (30 minutes after first bolus): 10 unit IV bolus over 2 minutes

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Reteplase in adult patients.

Non–Guideline-Supported Use

Vascular Graft Thrombosis
  • Dosing Information
  • 1 Unit in 2 mL and 3000 Units of heparin sodium [1]
Pulmonary Embolism
  • Dosing Information
  • First dose: 10 unit IV bolus over 2 minutes
  • Second dose (30 minutes after first bolus): 10 unit IV bolus over 2 minutes[2]
Acute Peripheral Ischemia
  • Dosing Information
  • 0.5-1.0 Units/hour (for approximately 20 hours)[3]

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Reteplase FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Reteplase in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Reteplase in pediatric patients.

Contraindications

  • Recent intracranial or intraspinal surgery or trauma

Warnings

Bleeding

  • The most common complication encountered during reteplase therapy is bleeding. The sites of bleeding include both internal bleeding sites (intracranial, retroperitoneal, gastrointestinal, genitourinary, or respiratory) and superficial bleeding sites (venous cutdowns, arterial punctures, sites of recent surgical intervention).
  • The concomitant use of heparin anticoagulation may contribute to bleeding.
  • In clinical trials some of the hemorrhage episodes occurred one or more days after the effects of reteplase had dissipated, but while heparin therapy was continuing.
  • As fibrin is lysed during reteplase therapy, bleeding from recent puncture sites may occur. Therefore, thrombolytic therapy requires careful attention to all potential bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites, and needle puncture sites).
  • Noncompressible arterial puncture must be avoided and internal jugular and subclavian venous punctures should be avoided to minimize bleeding from noncompressible sites.
  • Should an arterial puncture be necessary during the administration of reteplase, it is preferable to use an upper extremity vessel that is accessible to manual compression.
  • Pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.
  • Intramuscular injections and nonessential handling of the patient should be avoided during treatment with reteplase.
  • Venipunctures should be performed carefully and only as required.
  • Should serious bleeding (not controllable by local pressure) occur, concomitant anticoagulant therapy should be terminated immediately.
  • In addition, the second bolus of reteplase should not be given if serious bleeding occurs before it is administered.
  • Each patient being considered for therapy with reteplase should be carefully evaluated and anticipated benefits weighed against the potential risks associated with therapy.
  • In the following conditions, the risks of reteplase therapy may be increased and should be weighed against the anticipated benefits:

Cholesterol Embolization

Arrhythmias

Adverse Reactions

Clinical Trials Experience

Bleeding

  • The most frequent adverse reaction associated with reteplase is bleeding.
  • The types of bleeding events associated with thrombolytic therapy may be broadly categorized as either intracranial hemorrhage or other types of hemorrhage.

Intracranial hemorrhage

Other types of hemorrhage

  • The incidence of other types of bleeding events in clinical studies of reteplase varied depending upon the use of arterial catheterization or other invasive procedures and whether the study was performed in Europe or the USA.
  • The overall incidence of any bleeding event in patients treated with reteplase in clinical studies (n = 3,805) was 21.1%.
  • The rates for bleeding events, regardless of severity, for the 10 + 10 unit reteplase regimen from controlled clinical studies are summarized in Table 3.

Retavase hemorrahge rates.JPG

  • In these studies the severity and sites of bleeding events were comparable for reteplase and the comparison thrombolytic agents.
  • Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial) occur, any concomitant heparin should be terminated immediately.
  • In addition, the second bolus of reteplase should not be given if the serious bleeding occurs before it is administered.
  • Death and permanent disability are not uncommonly reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.
  • Fibrin which is part of the hemostatic plug formed at needle puncture sites will be lysed during reteplase therapy.
  • Therefore, reteplasetherapy requires careful attention to potential bleeding sites (e.g., catheter insertion sites, arterial puncture sites).

Allergic Reactions

  • Among the 2,965 patients receiving reteplase in the INJECT trial, serious allergic reactions were noted in 3 patients, with one patient experiencing dyspnea and hypotension.
  • No anaphylactoid reactions were observed among the 3,856 patients treated with reteplase in initial clinical trials.
  • In an ongoing clinical trial two anaphylactoid reactions have been reported among approximately 2,500 patients receiving reteplase.

Other Adverse Reactions

Postmarketing Experience

There is limited information regarding Reteplase Postmarketing Experience in the drug label.

Drug Interactions

  • The interaction of reteplase with other cardioactive drugs has not been studied.
  • In addition to bleeding associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as aspirin, dipyridamole, and abciximab) may increase the risk of bleeding if administered prior to or after reteplase therapy.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C Reteplase has been shown to have an abortifacient effect in rabbits when given in doses 3 times the human dose (0.86 units/kg). Reproduction studies performed in rats at doses up to 15 times the human dose (4.31 units/kg) revealed no evidence of fetal anomalies; however, Reteplase administered to pregnant rabbits resulted in hemorrhaging in the genital tract, leading to abortions in mid-gestation. There are no adequate and well-controlled studies in pregnant women. The most common complication of thrombolytic therapy is bleeding and certain conditions, including pregnancy, can increase this risk. Reteplase should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): C Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

Labor and Delivery

There is no FDA guidance on use of Reteplase during labor and delivery.

Nursing Mothers

It is not known whether reteplase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Retavase® is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of reteplase in pediatric patients have not been established.

Geriatic Use

There is no FDA guidance on the use of Reteplase in geriatric settings.

Gender

There is no FDA guidance on the use of Reteplase with respect to specific gender populations.

Race

There is no FDA guidance on the use of Reteplase with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Reteplase in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Reteplase in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Reteplase in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Reteplase in patients who are immunocompromised.

Administration and Monitoring

Administration

Reteplase is for intravenous administration only. Reteplase is administered as a 10 + 10 unit double-bolus injection. Two 10 unit bolus injections are required for a complete treatment. Each bolus is administered as an intravenous injection over 2 minutes. The second bolus is given 30 minutes after initiation of the first bolus injection. Each bolus injection should be given via an intravenous line in which no other medication is being simultaneously injected or infused. No other medication should be added to the injection solution containing reteplase. There is no experience with patients receiving repeat courses of therapy with reteplase.

Heparin and reteplase are incompatible when combined in solution. 'Do not administer heparin and reteplase simultaneously in the same intravenous line.'

If reteplase is to be injected through an intravenous line containing heparin, a normal saline or 5% dextrose (D5W) solution should be flushed through the line prior to and following the reteplase injection.

Although the value of anticoagulants and antiplatelet drugs during and following administration of reteplase has not been studied, heparin has been administered concomitantly in more than 99% of patients. Aspirin has been given either during and/or following heparin treatment. Studies assessing the safety and efficacy of reteplase without adjunctive therapy with heparin and aspirin have not been performed.

Reconstitution – Reteplase Kit and Reteplase Half-Kit: Reconstitution should be carried out using the diluent and dispensing pin provided with reteplase. It is important that reteplase be reconstituted only with the supplied Sterile Water for Injection, USP (without preservatives). The reconstituted preparation results in a colorless solution containing reteplase 1 unit/mL. Slight foaming upon reconstitution is not unusual; allowing the vial to stand undisturbed for several minutes is usually sufficient to allow dissipation of any large bubbles.

Because reteplase contains no antibacterial preservatives, it should be reconstituted immediately before use. When reconstituted as directed, the solution may be used within 4 hours when stored at 2-30°C (36-86°F). Prior to administration, the product should be visually inspected for particulate matter and discoloration.

Reconstitution Instructions-reteplase Kit and reteplase Half-Kit

Use aseptic technique throughout.

  • Step 1: Withdraw 10 mL of Sterile Water for Injection, USP (SWFI) from the supplied vial into a sterile 10 mL syringe.
  • Step 2: Open the package containing the dispensing pin. Remove the protective cap from the luer lock port of the dispensing pin and connect the sterile 10mL syringe to the dispensing pin. Remove the protective flip-cap from one vial of reteplase.
  • Step 3: Remove the protective cap from the spike end of the dispensing pin, and insert the spike into the vial of reteplase until the security clips lock onto the vial.

Transfer the 10 mL of SWFI through the dispensing pin into the vial of reteplase.

  • Step 4: With the dispensing pin and syringe still attached to the vial, swirl the vial gently to dissolve the reteplase. DO NOT SHAKE.
  • Step 5: Withdraw 10 mL of reteplase reconstituted solution back into the syringe. A small amount of solution will remain in the vial due to overfill.
  • Step 6: Detach the syringe from the dispensing pin, and attach a sterile needle.
  • Step 7: The 10 mL bolus dose is now ready for administration. Safely discard all used reconstitution components and the empty reteplase vial according to institutional procedures.

Monitoring

Drug/Laboratory Test Interactions
  • Administration of reteplase may cause decreases in plasminogen and fibrinogen. During reteplase therapy, if coagulation tests and/or measurements of fibrinolytic activity are performed, the results may be unreliable unless specific precautions are taken to prevent in vitro artifacts.
  • Reteplase is an enzyme that when present in blood in pharmacologic concentrations remains active under in vitro conditions.
  • This can lead to degradation of fibrinogen in blood samples removed for analysis.
  • Collection of blood samples in the presence of PPACK (chloromethylketone) at 2 µM concentrations was used in clinical trials to prevent in vitro fibrinolytic artifacts.
Use of Antithrombotics
  • Heparin and aspirin have been administered concomitantly with and following the administration of reteplase in the management of acute myocardial infarction.
  • Because heparin, aspirin, or reteplase may cause bleeding complications, careful monitoring for bleeding is advised, especially at arterial puncture sites.

IV Compatibility

  • Heparin and reteplase are incompatible when combined in solution
  • Do not administer heparin and reteplase simultaneously in the same intravenous line.

Overdosage

There is limited information regarding Reteplase overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Reteplase
Systematic (IUPAC) name
?
Identifiers
CAS number 133652-38-7
ATC code B01AD07
PubChem ?
DrugBank DB00015
Chemical data
Formula C1736H2671N499O522S22 
Mol. mass 39589.6 g/mol
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Pregnancy cat.

C

Legal status
Routes IV

Mechanism of Action

Reteplase is a recombinant plasminogen activator which catalyzes the cleavage of endogenous plasminogen to generate plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action.1,2In a controlled trial, 36 of 56 patients treated for an acute myocardial infarction (AMI) had a decrease in fibrinogen levels to below 100 mg/dL by 2 hours following the administration of reteplase as a double-bolus intravenous injection (10 + 10 unit) in which 10 units (17.4 mg) was followed 30 minutes later by a second bolus of 10 units (17.4 mg).3 The mean fibrinogen level returned to the baseline value by 48 hours.

Structure

Reteplase is a non-glycosylated deletion mutein of tissue plasminogen activator (tPA), containing the kringle 2 and the protease domains of human tPA. Reteplase contains 355 of the 527 amino acids of native tPA (amino acids 1-3 and 176-527). Reteplase is produced by recombinant DNA technology in E. coli. The protein is isolated as inactive inclusion bodies from E. coli, converted into its active form by an in vitro folding process and purified by chromatographic separation. The molecular weight of Reteplase is 39,571 daltons.

Pharmacodynamics

There is limited information regarding Reteplase Pharmacodynamics in the drug label.

Pharmacokinetics

Based on the measurement of thrombolytic activity, reteplase is cleared from plasma at a rate of 250-450 mL/min, with an effective half-life of 13-16 minutes. Reteplase is cleared primarily by the liver and kidney.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

  • Long-term studies in animals have not been performed to evaluate the carcinogenic potential of reteplase.
  • Studies to determine mutagenicity, chromosomal aberrations, gene mutations, and micronuclei induction were negative at all concentrations tested.
  • Reproductive toxicity studies in rats revealed no effects on fertility at doses up to 15 times the human dose (4.31 units/kg).

Clinical Studies

The safety and efficacy of reteplase were evaluated in three controlled clinical trials in which reteplase was compared to other thrombolytic agents. The INJECT study was designed to assess the relative effects of reteplase or the Streptase® brand of streptokinase upon mortality rates at 35 days following an AMI. The other studies (RAPID 1 and RAPID 2) were arteriographic studies which compared the effect on coronary patency of reteplase to two regimens of alteplase (a tissue plasminogen activator; Activase® in the USA and Actilyse® in Europe) in patients with an AMI. In all three studies, patients were treated with aspirin (initial doses of 160 mg to 350 mg and subsequent doses of 75 mg to 350 mg) and heparin (a 5,000 unit IV bolus prior to the administration of reteplase, followed by a 1000 unit/hour continuous IV infusion for at least 24 hours).3,4,5 The safety and efficacy of reteplase have not been evaluated using antithrombotic or antiplatelet regimens other than those described above.

Reteplase (10 + 10 unit) was compared to streptokinase (1.5 million units over 60 minutes) in a double-blind, randomized, European study (INJECT), which studied 6,010 patients treated within 12 hours of the onset of symptoms of AMI. To be eligible for enrollment, patients had to have chest pain consistent with coronary ischemia and ST segment elevation, or a bundle branch block pattern on the EKG. Patients with known cerebrovascular or other bleeding risks or those with a systolic blood pressure >200 mm Hg or a diastolic blood pressure >100 mm Hg were excluded from enrollment. The results of the primary endpoint (mortality at 35 days), six month mortality and selected other 35 day endpoints are shown in Table 1 for patients receiving study medications.

Clinicalpharmacology1.JPG

For mortality, stroke and the combined outcome of mortality or stroke, the 95% confidence intervals in Table 1 reflect the range within which the true difference in outcomes probably lies and includes the possibility of no difference. The incidences of congestive heart failure and of cardiogenic shock were significantly lower among patients treated with reteplase.

The total incidence of stroke was similar between the groups. However, more patients treated with reteplase experienced hemorrhagic strokes than patients treated with streptokinase. An exploratory analysis indicated that the incidence of intracranial hemorrhage was higher among older patients or those with elevated blood pressure. The incidence of intracranial hemorrhage among the 698 patients treated with reteplase who were older than 70 years was 2.2%. Intracranial hemorrhage occurred in 8 of the 332 (2.4%) patients treated with reteplase who had an initial systolic blood pressure >160 mm Hg and in 15 of the 2,629 (0.6%) reteplase patients who had an initial systolic blood pressure <160 mm Hg.

Two arteriographic studies (RAPID 1 and RAPID 2) were performed utilizing open-label administration of the study agents and a blinded review of the arteriograms. In RAPID 1, patients were treated within 6 hours of the onset of symptoms, and in RAPID 2, patients were treated within 12 hours of the onset of symptoms. Both studies evaluated coronary artery perfusion through the infarct-related artery 90 minutes after the initiation of therapy as the primary endpoint. Some patients in each study also had perfusion through the infarct-related artery evaluated at 60 minutes after the initiation of therapy. In RAPID 1, reteplase (in doses of 10 + 10 unit, 15 unit, or 10 + 5 unit) was compared to a 3 hour regimen of alteplase (100 mg administered over 3 hrs).In RAPID 2, reteplase (10 + 10 unit) was compared to an accelerated regimen of alteplase (100 mg administered over 1.5 hrs). The percentages of patients with partial or complete flow (TIMI grades 2 or 3) and complete flow (TIMI grade 3), are shown along with ventricular function assessments in Table 2. The follow-up arteriogram was performed at a median of 8 (RAPID 1) and 5 (RAPID 2) days following the administration of the thrombolytics. In RAPID 1 the best patency results were obtained with the 10 + 10 unit dose. In RAPID 2, the percentage of patients with partial or complete flow and the percentage of patients with complete flow was significantly higher with reteplase than with alteplaseat 90 minutes after the initiation of therapy. In both clinical trials the reocclusion rates were similar for reteplase and alteplase. The relationship between coronary artery patency and clinical efficacy has not been established.

Approximately 70% (RAPID 1) and 78% (RAPID 2) of the patients in the arteriographic studies underwent optional arteriography at 60 minutes following the administration of the study agents. In both trials the percentage of patients with complete flow at 60 minutes was significantly higher with reteplase than with alteplase. Neither RAPID clinical trial was designed nor powered to compare the efficacy or safety of reteplase and alteplase with respect to the outcomes of mortality and stroke.

Clinicalpharmacology2Retavase.JPG

How Supplied

Reteplase, is supplied as a sterile, preservative-free, lyophilized powder in 10.4 unit (equivalent to 18.1 mg reteplase) vials without a vacuum, in the following packaging configurations:

Reteplase Kit: 2 single-use reteplase vials 10.4 units (18.1 mg), 2 single-use diluent vials for reconstitution (10 mL Sterile Water for Injection, USP), 2 sterile 10 mL syringes, 2 sterile dispensing pins, 4 sterile needles, 2 alcohol swabs and a package insert;

Reteplase Half-Kit: 1 single-use reteplase vial 10.4 units (18.1 mg), 1 single-use diluent vial for reconstitution (10 mL Sterile Water for Injection, USP), a sterile dispensing pin and a package insert.

Rets.png

Storage

Store reteplase at 2-25°C (36-77°F). The box should remain sealed until use to protect the lyophilisate from exposure to light. Do not use beyond the expiration date printed on the box.

Images

Drug Images

Package and Label Display Panel

Rets1.JPG
This image of the FDA label is provided by the National Library of Medicine.
Reteplase.JPG
This image of the FDA label is provided by the National Library of Medicine.
Rets2.jpg
This image of the FDA label is provided by the National Library of Medicine.
Rets3.jpg
This image of the FDA label is provided by the National Library of Medicine.

Patient Counseling Information

There is limited information regarding Patient Counseling Information of Reteplase in the drug label.

Precautions with Alcohol

Alcohol-Reteplase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Retavase

Look-Alike Drug Names

There is limited information regarding Reteplase Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. A. Falk, J. Guller, F. S. Nowakowski, H. Mitty, V. Teodorescu, J. Uribarri & J. Vassalotti (2001). "Reteplase in the treatment of thrombosed hemodialysis grafts". Journal of vascular and interventional radiology : JVIR. 12 (11): 1257–1262. PMID 11698623. Unknown parameter |month= ignored (help)
  2. U. Tebbe, A. Graf, W. Kamke, R. Zahn, F. Forycki, G. Kratzsch & G. Berg (1999). "Hemodynamic effects of double bolus reteplase versus alteplase infusion in massive pulmonary embolism". American heart journal. 138 (1 Pt 1): 39–44. PMID 10385761. Unknown parameter |month= ignored (help)
  3. M. M. Davidian, A. Powell, J. F. Benenati, B. T. Katzen, G. J. Becker & G. Zemel (2000). "Initial results of reteplase in the treatment of acute lower extremity arterial occlusions". Journal of vascular and interventional radiology : JVIR. 11 (3): 289–294. PMID 10735421. Unknown parameter |month= ignored (help)

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