Retavase Information
Retavase (Reteplase) Description
Retavase (Reteplase) is a non-glycosylated deletion mutein of tissue plasminogen activator (tPA), containing the kringle 2 and the protease domains of human tPA. Retavase (Reteplase) contains 355 of the 527 amino acids of native tPA (amino acids 1-3 and 176-527). Retavase (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.
Potency is expressed in units (U) using a reference standard which is specific for Retavase (Reteplase) and is not comparable with units used for other thrombolytic agents.
Retavase (Reteplase) is a sterile, white, lyophilized powder for intravenous bolus injection after reconstitution with Sterile Water for Injection, USP (without preservatives). Following reconstitution, the pH is 6.0 ± 0.3. Retavase (Reteplase) is supplied as a 10.4 unit vial to ensure sufficient drug for administration of each 10 unit injection. Each single-use vial contains:
Reteplase 18.1 mg
Tranexamic Acid 8.32 mg
Dipotassium Hydrogen Phosphate 136.24 mg
Phosphoric Acid 51.27 mg
Sucrose 364.0 mg
Polysorbate 80 5.20 mg
Retavase (Reteplase) Clinical Pharmacology
General:
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Pharmacokinetics:
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Clinical Studies:
Retavase (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.
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 Retavase (Reteplase) .
The total incidence of stroke was similar between the groups. However, more patients treated with Retavase (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 Retavase (Reteplase) who were older than 70 years was 2.2%. Intracranial hemorrhage occurred in 8 of the 332 (2.4%) patients treated with Retavase (Reteplase) who had an initial systolic blood pressure >160 mm Hg and in 15 of the 2,629 (0.6%) Retavase (Reteplase) patients who had an initial systolic blood pressure
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, Retavase (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, Retavase (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 Retavase (Reteplase) than with Alteplase at 90 minutes after the initiation of therapy. In both clinical trials the reocclusion rates were similar for Retavase (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 Retavase (Reteplase) than with Alteplase. Neither RAPID clinical trial was designed nor powered to compare the efficacy or safety of Retavase (Reteplase) and Alteplase with respect to the outcomes of mortality and stroke.
Retavase (Reteplase) Indications And Usage
Retavase (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 (see ).
Retavase (Reteplase) Contraindications
Because thrombolytic therapy increases the risk of bleeding, Retavase (Reteplase) is contraindicated in the following situations:
Retavase (Reteplase) Warnings
Bleeding:
As fibrin is lysed during Retavase (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 Retavase (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 Retavase (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 Retavase (Reteplase) should not be given if serious bleeding occurs before it is administered.
Each patient being considered for therapy with Retavase (Reteplase) should be carefully evaluated and anticipated benefits weighed against the potential risks associated with therapy. In the following conditions, the risks of Retavase (Reteplase) therapy may be increased and should be weighed against the anticipated benefits:
Cholesterol Embolization:
Arrhythmias:
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Retavase (Reteplase) Precautions
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Readministration:
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Drug Interactions:
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Drug/Laboratory Test Interactions:
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Use of Antithrombotics:
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Carcinogenesis, Mutagenesis, Impairment of Fertility:
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Pregnancy Category C:
Nursing Mothers:
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Pediatric Use:
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Retavase (Reteplase) Adverse Reactions
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In these studies the severity and sites of bleeding events were comparable for Retavase (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 Retavase (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 Retavase (Reteplase) therapy. Therefore, Retavase (Reteplase) therapy requires careful attention to potential bleeding sites (e.g., catheter insertion sites, arterial puncture sites).
Allergic Reactions:
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Other Adverse Reactions:
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Retavase (Reteplase) Dosage And Administration
Retavase (Reteplase) is for intravenous administration only. Retavase (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 Retavase (Reteplase) . There is no experience with patients receiving repeat courses of therapy with Retavase (Reteplase) . Do not administer heparin and Retavase (Reteplase) simultaneously in the same intravenous line.
If Retavase (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 Retavase (Reteplase) injection.
Although the value of anticoagulants and antiplatelet drugs during and following administration of Retavase (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 Retavase (Reteplase) without adjunctive therapy with heparin and aspirin have not been performed.
Retavase (Reteplase) How Supplied
Retavase (Reteplase) , is supplied as a sterile, preservative-free, lyophilized powder in 10.4 unit (equivalent to 18.1 mg Retavase (Reteplase) ) vials without a vacuum, in the following packaging configurations:
Retavase (Reteplase) References
Retavase (Reteplase) ,Reteplase, recombinantManufactured by: EKR Therapeutics, Inc.Bedminster, NJ 07921U.S. License Number 1814
Manufactured at: Hospira, Inc., McPherson, KS 67460
For questions of a medical nature, call 1-877-207-5802.
© 2009 EKR Therapeutics, Inc. Revised February 2009 RET08-201
Retavase (Reteplase) Package Label - Principal Display Panel – Full Kit Carton
Retavase (Reteplase) Package Label - Principal Display Panel – Full Kit Vial
Retavase (Reteplase) Package Label - Principal Display Panel – Half Kit Carton
Retavase (Reteplase) Package Label - Principal Display Panel – Half Kit Vial
