Retavase

Contraindications

Hypersensitivity

Active bleeding, recent CVA, recent intracranial or intraspinal surgery or trauma, intracranial neoplasm, AVM, aneurysm, bleeding diathesis, severe uncontrolled HTN

See thrombolytic indications/contraindications

Cautions

Recent major surgery, cerebrovascular disease, recent GI or GU bleeding, HTN, acute pericarditis, hemostatic defects, severe thrombophlebitis, severe hepatic/renal dysfunction, currently receiving oral anticoagulants, diabetic hemorrhagic retinopathy, elderly

Monitor potential bleeding sites

Cholesterol embolism reported

Ischemic Stroke: may have no benefit if used after 3 hr of onset

Current use of warfarin and INR in high range may increase bleeding risk

Reteplase is injected into a vein through an IV. A healthcare provider will give you this injection.

Reteplase is usually given in two injections 30 minutes apart.

This medication can cause you to have unusual results with certain medical tests. Tell any doctor who treats you that you have received reteplase.

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Since reteplase is given only when needed by a healthcare professional, it is not likely that you will miss a dose.

Since retaplase is given only when needed by a healthcare professional, it is not likely that you will miss a dose.

Storage

Parenteral

2–25°C; protect from light.1

Reconstituted solutions contain no preservative.1 Preferably use solution immediately after preparation; may be used up to 4 hours after reconstitution if stored at 2–30°C.1 Discard any unused solution after 4 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Reteplase is incompatible with heparin.1

In the U.S.

• Retavase

Available Dosage Forms:

• Kit
• Powder for Solution

Therapeutic Class: Blood Modifier Agent

Pharmacologic Class: Tissue Plasminogen Activator

Retavase is indicated for use in acute ST-elevation myocardial infarction (STEMI) to reduce the risk of death and heart failure.

Limitation of Use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose STEMI puts them at low risk for death or heart failure.

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.

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 (reteplase) for Injection is a sterile, white, lyophilized powder for intravenous injection after reconstitution with Sterile Water for Injection, USP (without preservatives). Following reconstitution with 10 mL of Sterile Water for Injection, the resulting concentration is 1 unit/mL to allow for delivery of 10 mL (10 units reteplase). The pH is 6.0 ± 0.3. Retavase is supplied with overfill to ensure sufficient drug for administration of each 10 unit injection.

Each single-use vial delivers:

Retavase was evaluated in three controlled clinical studies comparing Retavase to other thrombolytic agents. 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 or control, followed by a 1000 unit/hour continuous IV infusion for at least 24 hours).

The INJECT study compared Retavase to streptokinase on mortality rates at 35 days following acute ST-elevation myocardial infarction (STEMI). INJECT was a double-blind study in which 6,010 patients with no more than 12 hours of chest pain consistent with coronary ischemia and either ST segment elevation or bundle branch block on ECG were randomized 1:1 to Retavase (10 + 10 unit) or streptokinase (1.5 million units over 60 minutes). Patients with cerebrovascular or other bleeding risks or with systolic blood pressure >200 mm Hg or diastolic blood pressure >100 mm Hg were excluded from enrollment. The study was designed to determine whether the effect of Retavase on survival was noninferior to that of streptokinase by ruling out with 95% confidence that 35-day mortality among Retavase patients was no more than 1% higher than among streptokinase patients. The results of the primary endpoint (mortality at 35 days), 6-month mortality, and selected other in-hospital endpoints are shown in Table 2.

Table 2: INJECT Study:  Selected Results

More patients treated with Retavase experienced hemorrhagic strokes than did 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 other two studies (RAPID 1 and RAPID 2) compared coronary artery patency of Retavase to two regimens of alteplase in patients with STEMI. In RAPID 1 patients within 6 hours of the onset of symptoms were randomized to open-label administration of one of three regimens of Retavase (doses of 10 + 10 unit, 15 unit, or 10 + 5 unit) or to alteplase (100 mg over 3 hours). In RAPID 2 patients within 12 hours of the onset of symptoms were randomized to open-label administration of either Retavase (10 + 10 unit) or alteplase (100 mg over 1.5 hours). The primary endpoint for both studies was patency of the infarct-related artery 90 minutes after initiation of therapy. Interpretation of coronary angiograms was blinded.

A higher percentage of subjects administered RETEVASE had complete flow (TIMI grade 3) and partial or complete flow (TIMI grades 2 or 3) compared to both regimens of alteplase. The relationship between coronary artery patency and clinical efficacy has not been established.

In both clinical trials the re-occlusion rates were similar for Retavase and alteplase.

Table 3: RAPID 1 and RAPID 2 Studies: Angiographic Results

Retavase (reteplase) for Injection is supplied as a sterile, preservative-free, lyophilized powder in 10 unit vials without a vacuum, in the following packaging configurations:

Retavase Kit (NDC 10122-141-02): 2 single-use Retavase vials 10 units, 2 single-use prefilled syringes for reconstitution (10 mL Sterile Water for Injection, USP), 2 syringe plungers, 2 sterile 10 mL graduated syringes, 2 sterile reconstitution spikes, 1 quick reference guide and 1 package insert.

Retavase Half-Kit (NDC 10122-143-01): 1 single-use Retavase vial 10 units, 1 single-use prefilled syringe for reconstitution (10 mL Sterile Water for Injection, USP), 1 syringe plunger, 1 sterile 10 mL graduated syringe, 1 sterile reconstitution spike, 1 quick reference guide and 1 package insert.

Storage: Store Retavase at 2°C to 25°C (36°F to 77°F). The box should remain sealed until use to protect the lyophilisate from exposure to light.

Distributed by:

Chiesi USA, Inc.                    

Cary, NC  27518

Manufactured by:

EKR Therapeutics, Inc.

Cary, NC 27518

U.S. License No. 1814

Retavase® manufactured at Actavis Italy, S.p.A. Nerviano, Italy 20014

To report an adverse event, record the lot number and call Medical Information at 1-888-661-9260.

Retavase® is a registered trademark of EKR Therapeutics, Inc.

The trademarks Streptase®, Activase®, and Actilyse® referenced herein are the property of their respective owners and are not affiliated with, connected to, or sponsored by Chiesi USA, Inc.

CTR-001-0415-00-SPL-1

Applies to reteplase: intravenous kit

Hematologic

Hematologic side effects have been the most frequently reported side effects. In the INJECT trial, the overall incidence of bleeds from any site was 15.0%, of which 4.6% were clinically significant. Transfusion requirements have ranged from 1.0% (INJECT trial) to 12.4% (RAPID-2 trial). The types of bleeds associated with this drug (and thrombolytic therapy, in general) may be broadly categorized as either intracranial hemorrhage or other types of hemorrhage.

The overall incidence of intracranial hemorrhage has averaged 0.8%. This risk is increased in patients with advanced age or hypertension. The incidence of transient ischemic attack (TIA) or reversible ischemic neurologic deficit (RIND) in the INJECT trial averaged 0.20%, and the incidence of frank stroke in the RAPID-2 trial averaged 1.8%. The average incidence of nonintracranial hemorrhage ranged from 1.9% to 9.0%, depending on the trial, use of arterial catheterization, and whether the study was performed in the US or Europe.

The incidence of IV site bleeding ranged from 4.6% to 48.6%. Arterial and venous punctures should be minimized. Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, or pericardial) occur, any concomitant heparin should be terminated immediately, and the second bolus of reteplase (the active ingredient contained in Retavase) should be withheld.[Ref]

The incidences of bleeding have been reported in the following sites within the following clinical trials, respectively (European INJECT study [n=2965], US RAPID-1 study [n=210], European RAPID-2 study [n=113]: injection site 4.6%, 48.6%, 19.5%; intracranial 1.2% (stroke), 0%, 1.8% (stroke); gastrointestinal 2.5%, 9.0%, 1.8%; genitourinary 1.6%, 9.5%, 0.9%; anemia 2.6%; 1.4%, 0.9%).

Since reteplase causes lysis of the fibrin plug, which is necessary to stop bleeding at puncture sites, careful attention should be paid to potential sites of bleeding during therapy (injection site, arterial puncture sites, catheter insertion sites, etc.).[Ref]

Cardiovascular

The following incidences were reported from the RAPID-2 trial: myocardial reinfarction 4.7%, congestive heart failure 9.5%, and ischemia or angina in 29.0%.

Cholesterol embolization--sometimes fatal--has been reported rarely in patients treated with thrombolytic agents. The exact incidence is unknown. Its relationship with lytic therapy might be coincidental as there is such risk associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.

Reperfusion arrhythmias during thrombolytic therapy can be a sign of successful lytic therapy. These arrhythmias (e.g., sinus bradycardia, accelerated idioventricular rhythm, ventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) may also be seen during the natural course of acute myocardial infarction, and they should be treated with standard antiarrhythmic measures, as indicated. It is recommended that antiarrhythmic therapy for bradycardia and/or ventricular irritability be available during reteplase (the active ingredient contained in Retavase) therapy.[Ref]

Cardiovascular side effects are probably sequelae of myocardial infarction and not due to reteplase. These side effects have included hypotension, cardiogenic shock, arrhythmias (e.g., sinus bradycardia, accelerated idioventricular rhythm, premature ventricular depolarizations, supraventricular tachycardia, ventricular tachycardia, and ventricular fibrillation), AV block, pulmonary edema, heart failure, cardiac arrest, recurrent ischemia, reinfarction, myocardial rupture, mitral regurgitation, pericardial effusion, pericarditis, cardiac tamponade, venous thrombosis and embolism, and electromechanical dissociation.[Ref]

Hypersensitivity

Serious hypersensitivity reactions to reteplase (the active ingredient contained in Retavase) have been rare. Among the 2,965 patients in the INJECT trial, such reactions were noted in 3 patients, with 1 patient experiencing dyspnea and hypotension. No cases of anaphylaxis were reported among the 3,856 patients treated with reteplase in initial clinical trials, but 2 cases of anaphylaxis were associated with the use of reteplase among approximately 2,500 patients in ongoing clinical trials.[Ref]

There are no data to demonstrate the formation of anti-reteplase antibodies among the approximately 2,400 patients who have been tested for the presence of such antibodies. Nevertheless, the use of reteplase (including the second bolus of reteplase) is not recommended if anaphylaxis has occurred with any prior use of reteplase in a given patient.[Ref]

Gastrointestinal

Gastrointestinal side effects have included nausea and vomiting.[Ref]

General

Fever, a general body side effect, has been reported.[Ref]

Some side effects of Retavase may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.