Retavase

EKR Therapeutics, Inc.
Hospira, Inc.

Retavase Reteplase, recombinant

FULL PRESCRIBING INFORMATION: CONTENTS*

• RETAVASE DESCRIPTION
• CLINICAL PHARMACOLOGY
• RETAVASE INDICATIONS AND USAGE
• RETAVASE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
• RETAVASE ADVERSE REACTIONS
• RETAVASE DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• References
• Package Label - Principal Display Panel – Full Kit Carton
• Package Label - Principal Display Panel – Full Kit Vial
• Package Label - Principal Display Panel – Half Kit Carton
• Package Label - Principal Display Panel – Half Kit Vial

FULL PRESCRIBING INFORMATION

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^® contains 355 of the 527 amino acids of native tPA (amino acids 1-3 and 176-527). Retavase^® 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^® and is not comparable with units used for other thrombolytic agents.

Retavase^® 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^® 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

CLINICAL PHARMACOLOGY

General: Retavase^® 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.^1,2 In 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 Retavase^® 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.

Clinical Studies: The safety and efficacy of Retavase^® were evaluated in three controlled clinical trials in which Retavase^® was compared to other thrombolytic agents. The INJECT study was designed to assess the relative effects of Retavase^® 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 Retavase^® 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 Retavase^®, followed by a 1000 unit/hour continuous IV infusion for at least 24 hours).^3,4,5 The safety and efficacy of Retavase^® have not been evaluated using antithrombotic or antiplatelet regimens other than those described above.

Retavase^® (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^®.

The total incidence of stroke was similar between the groups. However, more patients treated with Retavase^® 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^® who were older than 70 years was 2.2%. Intracranial hemorrhage occurred in 8 of the 332 (2.4%) patients treated with Retavase^® who had an initial systolic blood pressure >160 mm Hg and in 15 of the 2,629 (0.6%) Retavase^® 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, Retavase^® (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^® (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^® than with Alteplase at 90 minutes after the initiation of therapy. In both clinical trials the reocclusion rates were similar for Retavase^® 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^® than with Alteplase. Neither RAPID clinical trial was designed nor powered to compare the efficacy or safety of Retavase^® and Alteplase with respect to the outcomes of mortality and stroke.

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 CLINICAL PHARMACOLOGY ).

CONTRAINDICATIONS

Because thrombolytic therapy increases the risk of bleeding, Retavase^® is contraindicated in the following situations:

• Active internal bleeding
• History of cerebrovascular accident
• Recent intracranial or intraspinal surgery or trauma (see WARNINGS)
• Intracranial neoplasm, arteriovenous malformation, or aneurysm
• Known bleeding diathesis
• Severe uncontrolled hypertension

WARNINGS

PRECAUTIONS

General: Standard management of myocardial infarction should be implemented concomitantly with Retavase^® treatment. Arterial and venous punctures should be minimized (see WARNINGS ). In addition, the second bolus of Retavase^® should not be given if the serious bleeding occurs before it is administered. In the event of serious bleeding, any concomitant heparin should be terminated immediately. Heparin effects can be reversed by protamine.

Drug Interactions: The interaction of Retavase^® 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 Retavase^® therapy.

Drug/Laboratory Test Interactions: Administration of Retavase^® may cause decreases in plasminogen and fibrinogen. During Retavase^® 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. Retavase^® 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.⁶

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Retavase.^® 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).

Nursing Mothers: It is not known whether Retavase^® 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 Retavase^® in pediatric patients have not been established.

ADVERSE REACTIONS

DOSAGE AND ADMINISTRATION

Retavase^® (Reteplase) is for intravenous administration only. Retavase^® 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^®. There is no experience with patients receiving repeat courses of therapy with Retavase^®. Heparin and Retavase^® are incompatible when combined in solution. Do not administer heparin and Retavase^® simultaneously in the same intravenous line.

If Retavase^® 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^® injection.

Although the value of anticoagulants and antiplatelet drugs during and following administration of Retavase^® 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^® without adjunctive therapy with heparin and aspirin have not been performed.

HOW SUPPLIED

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

Retavase^® Kit: 2 single-use Retavase^® 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;

Retavase^® Half-Kit: 1 single-use Retavase^® 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.

Storage: Store Retavase^® 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.

References

• Martin U, Sponer G, Strein K. Evaluation of thrombolytic and systemic effects of the novel recombinant plasminogen activator BM 06.022 compared with alteplase, anistreplase, streptokinase and urokinase in a canine model of coronary artery thrombosis. JACC. 1992;19:433-440.
• Kohnert U, Rudolph R, Verheijen JH. Biochemical properties of the kringle 2 and protease domains are maintained in the refolded t-PA deletion variant BM 06.022. Protein Engineering. 1992;5:93-100.
• Smalling R, 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. Circulation. 1995;91:2725-2732.
• Bode C, Smalling R, Gunther B, 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;94:891-898.
• INJECT Study Group. Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet. 1995;346:329-336.
• Martin U, Gärtner D, Markl HJ, et al. D-PHE-PRO-ARGCHLOROMETHYLKETONE prevents in vitro fibrinogen reduction by the novel recombinant plasminogen activator BM 06.022. Ann Hematol. 1992;64(suppl)A47.

Retavase^®,
Reteplase, recombinant
Manufactured by: EKR Therapeutics, Inc.
Bedminster, NJ 07921
U.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

Package Label - Principal Display Panel – Full Kit Carton

Package Label - Principal Display Panel – Full Kit Vial

Package Label - Principal Display Panel – Half Kit Carton

Package Label - Principal Display Panel – Half Kit Vial