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Reteplase, Recombinant (Systemic)


VA CLASSIFICATION
Primary: BL115

Commonly used brand name(s): Retavase.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Thrombolytic—

Indications

Accepted

Thrombosis, coronary arterial, acute (treatment)—Reteplase is indicated for use in the management of acute myocardial infarction (AMI) in adults to improve ventricular function following AMI, reduce the incidence of congestive heart failure, and reduce mortality associated with AMI. {01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Reteplase is a nonglycosylated deletion mutein of tissue plasminogen activator produced by recombinant DNA technology in Escherichia coli , and purified by chromatographic separation {01}
Molecular weight—
    39,571 daltons {01}

Mechanism of action/Effect:

Reteplase catalyzes the cleavage of endogenous plasminogen to generate plasmin, which in turn degrades the fibrin matrix of the thrombus, resulting in thrombolysis. {01}

Half-life:

Elimination, effective, based on the measurement of thrombolytic activity—13 to 16 minutes. {01}

Time to peak effect:

In a controlled trial, 36 of 56 patients treated for an acute myocardial infarction had a decrease in fibrinogen concentrations to below 100 mg per dL within 2 hours following double-bolus administration of reteplase. {01}

Duration of action:

After an initial decrease in fibrinogen concentrations following double-bolus administration of reteplase, the mean fibrinogen concentration returned to the baseline value by 48 hours. {01}

Elimination:
    Hepatic and renal. {01}


Precautions to Consider

Carcinogenicity

Long-term studies to evaluate the carcinogenic potential of reteplase have not been done. {01}

Mutagenicity

Studies to determine mutagenicity, chromosomal aberrations, gene mutations, and micronuclei induction were negative at all concentrations tested. {01}

Pregnancy/Reproduction
Fertility—
Studies in rats revealed no effects on fertility at doses up to 15 times the human dose (4.31 units per kg [Units/kg]). {01}

Pregnancy—
Studies have not been done in humans. {01}

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. {01}

Reteplase has been shown to have an abortifacient effect in rabbits when given in doses three times the human dose (0.86 Units/kg). Administration to pregnant rabbits resulted in hemorrhaging in the genital tract leading to abortions in mid-gestation. Studies in rats at doses up to 15 times the human dose (4.31 Units/kg) revealed no evidence of fetal anomalies. {01}

FDA Pregnancy Category C. {01}

Breast-feeding

It is not known whether reteplase is distributed into breast milk. However, problems in humans have not been documented. {01}

Pediatrics

No information is available on the relationship of age to the effects of reteplase in pediatric patients. Safety and efficacy have not been established. {01}


Geriatrics


The risk of intracranial hemorrhage and other types of hemorrhage is increased in patients of advanced age. Patients should be carefully evaluated and the anticipated benefits of reteplase therapy should be weighed against the potential risks. {01}


Critical/Emergency care

Standard management of myocardial infarction should be implemented concomitantly with reteplase. Arterial and venous punctures should be minimized. Noncompressible arterial puncture must be avoided and internal jugular and subclavian venous punctures should be avoided to minimize bleeding. 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. Venipunctures should be performed carefully and only as required. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anticoagulants, coumarin- or indandione-derivative or
» Heparin or
» Platelet aggregation inhibitors (See Appendix II ), such as:
Abciximab
Aspirin
Dipyridamole    (the risk of bleeding may be increased when these agents are administered prior to or after reteplase therapy; however, heparin and aspirin have been administered concomitantly with and following the administration of reteplase in the management of acute myocardial infarction; careful monitoring for bleeding is recommended, especially at arterial puncture sites)

{01}

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Coagulation tests and
Tests for systemic fibrinolysis    (reteplase, when present in blood in pharmacologic concentrations, remains active under in vitro conditions, which can lead to degradation of fibrinogen in blood samples removed for analysis; therefore, results of these tests may be unreliable unless specific precautions are taken to prevent in vitro fibrinolytic artifacts)

{01}
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Aneurysm, intracranial or
» Arteriovenous malformation or
» Bleeding, active or
» Brain tumor or
» Cerebrovascular accident, or history of or
» Hemostatic disorders or
» Neurosurgery, intracranial or intraspinal, recent or
» Trauma to the central nervous system (CNS), recent    (increased risk of uncontrollable hemorrhage)

{01}
» Hypertension, severe uncontrolled    (increased risk of cerebral hemorrhage)

{01}
Risk-benefit should be considered when the following medical problems exist
Any condition in which the risk of bleeding or hemorrhage is present or would be difficult to control because of its location, such as:{01}
Cerebrovascular disease
» Childbirth, recent
» Coagulation defects, uncontrolled, or other hemostatic defects, including those secondary to severe hepatic or renal disease
» Endocarditis, bacterial, subacute
» Gastrointestinal bleeding, recent
Genitourinary bleeding, recent
Hemorrhagic retinopathy, diabetic or other hemorrhagic ophthalmic conditions
Hepatic function impairment, severe
Hypertension, moderate, not optimally controlled, i.e., ³ 180 mm Hg systolic and/or ³ 110 mm Hg diastolic
» Organ biopsy, recent
Pregnancy
» Puncture of noncompressible blood vessel, recent
Renal function impairment, severe
» Surgery, major, recent
» Trauma, recent
Infection at or near site of thrombus, obstructed intravenous catheter, or occluded arteriovenous cannula    (risk of spreading the infection into and via the circulation)

{01}
» Mitral stenosis with atrial fibrillation or other indications of probable left heart thrombus    (risk of new embolic phenomena including those to cerebral vessels)

{01}
Pericarditis, acute    (risk of hemopericardium, which may lead to cardiac tamponade)

{01}


Side/Adverse Effects

Note: Bleeding, the most common side effect encountered during reteplase therapy, occurs both internally (intracranial, retroperitoneal, gastrointestinal, genitourinary, or respiratory) and superficially (venous cutdowns, arterial punctures, sites of recent surgical intervention). Bleeding may occur from recent puncture sites as fibrin is lysed during therapy with reteplase. The risk of intracranial hemorrhage is increased in patients of advanced age or with elevated blood pressure. {01}
Cardiac arrhythmias may occur during or following coronary thrombolysis. These are not necessarily direct effects of the medication and may be associated with the myocardial infarction itself, or may be induced by sudden reperfusion. Specific arrhythmias that have been reported include sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, supraventricular tachycardia, ventricular tachycardia, and ventricular fibrillation. {01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Bleeding or oozing from cuts, invaded or disturbed sites, wounds, or gums {01}

Incidence less frequent or rare
    
Allergic reaction (flushing or redness of skin; mild headache; mild muscle pain; nausea; skin rash, hives, or itching; troubled breathing or wheezing){01}
    
cholesterol embolism {01}
    
fever {01}
    
hypotension {01}
    
internal bleeding (abdominal pain or swelling; back pain or backaches; bloody urine; bloody or black, tarry stools; constipation caused by hemorrhage-induced paralytic ileus or intestinal obstruction; coughing up blood; dizziness; headaches, sudden, severe, and/or continuing; joint pain, stiffness, or swelling; muscle pain or stiffness, severe or continuing; nosebleeds; unexpected or unusually heavy bleeding from vagina; vomiting of blood or material that looks like coffee grounds){01}
    
stroke, hemorrhagic (confusion; double vision; impairment of speech; weakness in arms or legs){01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Nausea and/or vomiting {01}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Thrombolytic Agents (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:





Use in the elderly—Increased risk of hemorrhage
Other medications, especially anticoagulants, heparin, and platelet aggregation inhibitors
Other medical problems, especially conditions leading to an increased risk of uncontrollable or cerebral hemorrhage, and mitral stenosis

Proper use of this medication

» Proper dosing

Precautions while using this medication
» Importance of compliance with strict bed rest or other measures to minimize bleeding


Side/adverse effects
Signs of potential side effects, especially bleeding or oozing from cuts, invaded or disturbed sites, wounds, or gums; allergic reaction; cholesterol embolism; fever; hypotension; internal bleeding; and hemorrhagic stroke


General Dosing Information
The potency of reteplase is expressed in units using a reference standard that is specific for reteplase and is not comparable with units used for other thrombolytic agents. {01}

Intramuscular injections and nonessential handling of the patient should be avoided during treatment with reteplase to minimize bleeding. {01}

Reteplase should be given via an intravenous line in which no other medication is being simultaneously injected or infused. {01}

There is no experience with patients receiving repeat courses of therapy with reteplase. Reteplase did not induce the formation of reteplase-specific antibodies in any of the patients who were tested for antibody formation in clinical trials. {01}

For treatment of adverse effects
Recommended treatment consists of the following:
   • For anaphylactoid reactions—The second bolus of reteplase should not be given, and appropriate therapy should be initiated. {01}
   • For serious bleeding (not controllable by local pressure)—Concomitant anticoagulant therapy should be terminated immediately. Heparin effects can be reversed with protamine. In addition, the second bolus of reteplase should not be given if the serious bleeding occurs before it is administered. {01}
   • For reperfusion arrhythmias—Standard antiarrhythmic measures should be followed. It is recommended that antiarrhythmic therapy for bradycardia and/or ventricular irritability be available when reteplase is administered. {01}


Parenteral Dosage Forms

RETEPLASE, RECOMBINANT FOR INJECTION

Note: Reteplase is administered as a double-bolus injection. {01}


Usual adult dose
Thrombosis, coronary arterial, acute
Intravenous, 10 units administered over two minutes. The second 10-unit dose is given thirty minutes after initiation of the first injection. {01}


Usual pediatric dose
Safety and efficacy have not been established. {01}

Strength(s) usually available
U.S.—


10.8 units (18.8 mg) per single-dose vial (Rx) [Retavase (supplied as a kit containing 2 single-dose reteplase vials, 2 single-dose diluent vials for reconstitution [10 mL Sterile Water for Injection USP], 2 sterile 10 mL syringes with 20-gauge needle attached, 2 sterile dispensing pins, 2 sterile 20-gauge needles for dose administration, and 2 alcohol swabs)]

Packaging and storage:
Store between 2 and 25 °C (36 and 77 °F). Protect from light. {01}

Preparation of dosage form:
Reteplase should be reconstituted only with Sterile Water for Injection USP (without preservatives). The reconstituted preparation results in a colorless solution containing reteplase 1 unit per mL. Slight foaming may occur during reconstitution; however, large bubbles dissipate when the solution is left undisturbed for a few minutes. The following steps should be taken for reconstitution: {01}
   #149; Withdraw 10 mL of Sterile Water for Injection USP from the vial using the 10 mL syringe with attached needle.
   #149; Remove and discard the needle and connect the syringe to the dispensing pin via the Luer-lock port.
   #149; Insert the spike end of the dispensing pin into the vial of reteplase and transfer the 10 mL of Sterile Water for Injection USP.
   #149; Swirl the vial gently to dissolve the reteplase, with the dispensing pin and syringe still attached to the vial.
   #149; Withdraw 10 mL of the reconstituted reteplase solution back into the syringe. A small amount of solution will remain in the vial due to overfill.
   #149; Detach the syringe from the dispensing pin and attach the sterile 20-gauge needle provided. The 10-mL dose is now ready for administration.

Stability:
The reconstituted solution should be used within 4 hours when stored between 2 and 30 °C (36 and 86 °F). It should be discarded if not used within this time. However, because reteplase for injection contains no preservatives, it should not be reconstituted until immediately prior to use. Any unused solution must be discarded. {01}

Incompatibilities:
Do not add any other medication to the container of reteplase solution or administer other medications through the same intravenous line. Heparin and reteplase are incompatible when combined in solution. If reteplase is to be injected through an intravenous line containing heparin, a 0.9% sodium chloride or 5% dextrose solution should be flushed through the line prior to and following the reteplase injection. {01}



Developed: 05/14/1997



References
  1. Retavase package insert (Boehringer Mannheim—US), Rev 11/96, Rec 1/97.
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