2.1 Dosing Information and Administration

As soon as possible after the onset of STEMI, administer 10 units intravenously over 2 minutes. Administer a second dose of 10 units 30 minutes after the first dose.

2.2 Reconstitution

Reconstitute RETAVASE immediately before administration.

Reconstitute RETAVASE only with the supplied Sterile Water for Injection. Slight foaming upon reconstitution may occur; if necessary allow the vial to stand undisturbed for several minutes to allow dissipation of any large bubbles. Prior to administration, inspect the product for particulate matter and discoloration.

Use aseptic technique throughout.

Step 1: Open the package containing the reconstitution spike. Remove the protective cap from the luer lock port of the reconstitution spike and remove the protective cap on the end of the sterile 10 mL pre-filled syringe. Remove the protective flip-cap from one vial of RETAVASE.

Step 2: Clean the rubber closure with an alcohol wipe (not contained within kit).

Step 3: Connect the sterile pre-filled syringe to the reconstitution spike.

Step 4: Remove the protective cap from the spike end of the reconstitution spike and firmly insert the spike into the vial of RETAVASE.

Step 5: Connect the syringe plunger to the sterile 10 mL pre-filled syringe by screwing the plunger into the rubber stopper.

Step 6: Transfer the 10 mL of Sterile Water for Injection through the reconstitution spike into the vial of RETAVASE.

Step 7: With the reconstitution spike and empty pre-filled syringe still attached to the vial, swirl the vial gently until the contents are fully dissolved, may take up to 2 minutes. DO NOT SHAKE. Upon reconstitution, the solution should be clear and colorless. Discard if particulate matter or discoloration is observed. The resulting solution concentration is 1 unit/mL and delivers 10 mL (10 units reteplase).

Step 8: Disconnect the empty pre-filled syringe from the reconstitution spike and connect the plastic, graduated syringe to the reconstitution spike that is still attached to the vial.

Step 9: Withdraw 10 mL of RETAVASE reconstituted solution into the graduated syringe. A small amount of solution will remain in the vial due to overfill. Detach the graduated syringe from the reconstitution spike.

2.3 Heparin Incompatibility

Heparin and RETAVASE are incompatible. Do not administer RETAVASE through an intravenous line containing heparin.

5.1 Bleeding

RETAVASE can cause significant and sometimes fatal bleeding. Avoid intramuscular injections and other trauma to a patient administered RETAVASE. Minimize venipunctures. Avoid puncturing noncompressible veins, such as the internal jugular and subclavian. If an arterial puncture is necessary, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. As fibrin is lysed during RETAVASE therapy, bleeding from recent puncture sites or other recent trauma may occur.

Should serious bleeding (not controllable by local pressure) occur, terminate concomitant anticoagulant therapy. Withhold the second RETAVASE dose if serious bleeding occurs before it is administered.

5.2 Hypersensitivity Reactions

Hypersensitivity reactions have been reported with RETAVASE administration. Signs and symptoms observed included rash, pruritis, erythema, glossal (tongue) edema, hypotension and respiratory distress. If an anaphylactoid reaction occurs, withhold the second dose of RETAVASE and initiate appropriate therapy.

5.3 Cholesterol Embolization

Cholesterol embolism has been reported in patients treated with thrombolytic agents. Cholesterol embolism may present with livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis and can be fatal. It is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.

5.4 Drug/Laboratory Test Interactions

Coagulation tests and measures of fibrinolytic activity are unreliable during RETAVASE therapy unless specific precautions are taken to prevent in vitro artifacts. When present in blood at pharmacologic concentrations, RETAVASE remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Bleeding

The most frequent adverse reaction associated with RETAVASE is bleeding.

• Intracranial hemorrhage [see Clinical Studies (14)]

In the INJECT clinical trial, the overall rate of in-hospital, intracranial hemorrhage was 0.8%. The risk for intracranial hemorrhage is increased in patients with advanced age (2.2% among patients >70 years old) or with elevated blood pressure (2.4% among patients with systolic blood pressure >160 mmHg).

• Other types of hemorrhage

The incidence of other types of bleeding events in clinical studies of RETAVASE 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 RETAVASE in clinical studies (n = 3,805) was 21.1%. The rates for bleeding events, regardless of severity, for the 10 + 10 unit RETAVASE regimen from controlled clinical studies are summarized in Table 1.

Table 1: RETAVASE Hemorrhage Rates

In these studies the severity and sites of bleeding events were similar for RETAVASE and the comparison thrombolytic agents.

Allergic Reactions

Among the 2,965 patients receiving RETAVASE in the INJECT trial, serious allergic reactions were noted in 3 patients, with one patient experiencing dyspnea and hypotension.

Among the 9,938 patients that received RETAVASE in a postmarketing clinical study, 8 patients experienced allergic and/or anaphylactoid reactions. Signs and symptoms observed included rash, pruritis, erythema, glossal (tongue) edema, hypotension, and respiratory distress.

8.1 Pregnancy

Risk Summary

Limited published data with RETAVASE use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies, reteplase administered to pregnant rabbits resulted in hemorrhaging in the genital tract, leading to abortions in mid-gestation in doses 3 times the human dose; however, there was no evidence of fetal anomalies in rats at doses up to 15 times the human dose.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Maternal Adverse Reactions

The most common complication of thrombolytic therapy is bleeding and pregnancy may increase this risk.

Data

Animal Data

Reteplase was administered to pregnant rabbits in doses 3 times the human dose (0.86 units/kg) resulting in hemorrhaging in the genital tract, leading to abortions in mid-gestation. In animal developmental studies in rats at Reteplase doses up to 15 times the human dose (4.31 units/kg), there was no evidence of fetal anomalies.

8.2 Lactation

Risk Summary

There are no data on the presence of reteplase in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. RETEVASE has not been studied in nursing mothers.

8.4 Pediatric Use

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

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

In a controlled trial, 36 of 56 patients treated for myocardial infarction had a decrease in fibrinogen levels to below 100 mg/dL by 2 hours following the administration of RETAVASE as two intravenous injections (10 + 10 unit) in which 10 units was followed 30 minutes later by a second dose of 10 units. The mean fibrinogen level returned to the baseline value by 48 hours.

12.3 Pharmacokinetics

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

13.1 Carcinogenesis and Mutagenesis

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.