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Intravenous Dilution Guidelines

Reteplase (Retavase® )

The authors make no claims of the accuracy of the information contained herein; and these suggested doses and/or guidelines are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this document shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.    PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.

Usual Diluents

NS

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

Management of acute MI:
[10 units] [10 mL - Sterile Water for Inj (supplied)] [2 minutes]

Catheter-directed thrombolytic therapy:
[5 – 10 units] [100 – 500 ml]
[Usual: 0.25 to 1 unit/hr]

Sample dilutions:
10 units/ 100 ml
10 units/ 250 ml

Double lumen catheter:
5 units/100 ml x 2 bags.
Alternatively:
5 units/250 ml x 2 bags.

Stability / Miscellaneous


---- Storage/Stability ----

Management of acute MI (Bolus dose): 4 hours RT.
Catheter-directed thrombolytic therapy (continuous infusion): IV Admixture stability: Once reconstituted, per documented studies, the solution is stable for only 24 hours at room temperature.

Some studies indicate that the 0.01 U/ml [e.g. 10 units/ 500 ml] reteplase solution is both physically and biochemically stable when stored at room temperature for up to 24 hours.

Because Retavase® contains no antibacterial preservatives, it should be reconstituted immediately before use. When reconstituted as directed, the solution may be used within 4 hours when stored at 2-30°C (36-86°F). Prior to administration, the product should be visually inspected for particulate matter and discoloration.

DOSING (Adult):
Retavase® (Reteplase) is for intravenous administration only. Retavase® is administered as a 10 + 10 U double-bolus injection. 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.

Reconstitution should be carried out using the diluent and dispensing pin provided with Retavase®. It is important that Retavase® be reconstituted only with the supplied Sterile Water for Injection, USP (without preservatives). The reconstituted preparation results in a colorless solution containing Retavase® 1 unit/mL. Slight foaming upon reconstitution is not unusual; allowing the vial to stand undisturbed for several minutes is usually sufficient to allow dissipation of any large bubbles.

Reconstitution Instructions Retavase® Kit and Retavase® Half-Kit: Use aseptic technique throughout.
Step 1:
Withdraw 10 mL of Sterile Water for Injection, USP (SWFI) from the supplied vial into a sterile 10 mL syringe.
Step 2:
Open the package containing the dispensing pin.
Remove the protective cap from the luer lock port of the dispensing pin and connect the sterile 10mL syringe to the dispensing pin.
Remove the protective flip-cap from one vial of Retavase®.
Step 3:
Remove the protective cap from the spike end of the dispensing pin, and insert the spike into the vial of Retavase® until the security clips lock onto the vial.
Transfer the 10 mL of SWFI through the dispensing pin into the vial of Retavase®.
Step 4:
With the dispensing pin and syringe still attached to the vial, swirl the vial gently to dissolve the Retavase®. DO NOT SHAKE.
Step 5:
Withdraw 10 mL of Retavase® reconstituted solution back into the syringe. A small amount of solution will remain in the vial due to overfill.
Step 6: Detach the syringe from the dispensing pin, and attach a sterile needle.
Step 7: The 10 mL bolus dose is now ready for administration.

Safely discard all used reconstitution components and the empty Retavase® vial according to institutional procedures.

Background:
Reteplase retains fibrin specificity and preferentially converts clot-bound plasminogen rather than free plasminogen.

Compared to tPA, reteplase has a lower fibrin binding which may translate into improved clot penetration.

In PAD various doses have been used. One study used 0.125, 0.25 and 0.5 units/hr. the lower rate had longer infusion times, while the 0.5 group had significantly higher bleeding rates. Efficacy was essentially the same. Study optimal dose: 0.25 units/hr. a consensus conference recommended a reteplase dose of 0.25 to 1.0 units/hr, with or without an initial bolus of 2 – 5 units. A total dose of</= 20 units for tx of peripheral occlusion was believed to be appropriate. Plasminogen activators are classified as fibrin-specific or non-fibrin specific agents. Streptokinase and urokinase are non-fibrin specific and alteplase, reteplase, and tenecteplase are fibrin-specific agents.

For the treatment of acute peripheral arterial thromboembolism:
Intravenous dosage:
Adults: According to information from the manufacturer, the most common regimen is a continuous infusion of reteplase 0.5 - 1 units/hour IV for 5 - 24 hours with a concurrent infusion of heparin in subtherapeutic doses. In some cases the IV infusion was preceded by lacing or infiltrating the clot with a 2 - 5 unit IV bolus of reteplase. When heparin has been used, it is usually given as a low-dose IV bolus or as a continuous infusion at 100 - 500 units/hour IV. Some cases have been managed without heparin. Reteplase and heparin should be administered through separate intravenous or intravascular lines. In 2 cases, pedal pulses returned within 45 minutes to 2 hours after initiating therapy, and in several cases, the infusion was discontinued after 5 hours due to clot lysis. The adverse events in these patients appears to be similar to that observed among patients receiving other thrombolytic agents for this indication. There have been reports of major bleeding primarily associated with prolonged (> 24 hours) infusions and with the use of concomitant anticoagulant therapy (i.e., heparin). (written communication, Centocor)

For reestablishing patency of an occluded IV catheter or occluded dialysis access catheters: Adults: Different techniques have been used. Current information from the manufacturer suggests a dose of 0.4 units of reteplase solution, expanded to the volume of the catheter with normal saline; the solution should be instilled into the catheter to dwell for at least 30 minutes, then removed by aspiration. Alternative regimens include instillation of 0.5 - 1 unit reteplase into the catheter to dwell for 20 minutes, after which time the solution is removed by aspiration. (written communication, Centocor)

For clearing a totally or partially occluded arteriovenous (AV) cannula (e.g., shunts or fistulas): Adults: The manufacturer reports several different techniques have been used to treat clotted access grafts (shunts or fistulas) used for hemodialysis. In one series of 18 patients, dialysis grafts were accessed using an 18 gauge Angiocath™ and instilled with either 2 units (n=3) or 3 units (n=15) of reteplase diluted in 7 ml of normal saline. All patients received 3000 IU heparin. After waiting 30 - 60 minutes after instillation of reteplase, a routine AV graft angiogram was performed. Of the 15 patients treated with reteplase 3 units, all had successful lysis of the occlusion. Only one of the patients treated with reteplase 2 units had successful lysis without adjunctive treatment. (written communication, Centocor)

Fibrinolytic agents
Variable Streptokinase Alteplase tPA* Reteplase rPA Tenecteplase TNK-tPA
Half-Life (alpha) min 18-23 min 4-8 min 15 min (13-16) 20 min 
(20 - 24)
Molecular weight 47,000 70,000 39,000
70,000
Administration Infusion (1.5 MU over 30 minutes) Infusion (weight based up to 100 mg over 90 minutes) 10 units over 2 min repeated after 30 minutes Weight adjusted bolus 30-50 mg over 5–10 seconds

< 60 kg: 30 mg
60–69.9 kg: 35 mg
70–79.9 kg: 40 mg
80–89.9 kg: 45 mg
> 90 kg: 50 mg
Fibrin specific No Yes++ Yes+ Yes+++
Systemic fibrinogen depletion +++ + ++ Minimal
Bleeding (non-cerebral) +++ ++ ++ +
Thrombolytic Potency   + ++ +++
PAI-1
Inhibition
  ++ +++ +
Hemorrhagic stroke + ++ ++ ++
Antigenic Yes No No No
Hypotension with administration Yes No No No
TIMI grade 3 flow at 90 minutes (%) 32 54 60 63
Cost + ++ +++ ++++
   
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
Bleeding: The most common complication encountered during Retavase® therapy is bleeding. The sites of bleeding include both internal bleeding sites (intracranial, retroperitoneal, gastrointestinal, genitourinary, or respiratory) and superficial bleeding sites (venous cutdowns, arterial punctures, sites of recent surgical intervention). The concomitant use of heparin anticoagulation may contribute to bleeding. In clinical trials some of the hemorrhage episodes occurred one or more days after the effects of Retavase® had dissipated, but while heparin therapy was continuing. As fibrin is lysed during Retavase® 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®, 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®. 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® should not be given if serious bleeding occurs before it is administered. Each patient being considered for therapy with Retavase® should be carefully evaluated and anticipated benefits weighed against the potential risks associated with therapy.


In the following conditions, the risks of Retavase® therapy may be increased and should be weighed against the anticipated benefits
:

• Recent major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy
• Previous puncture of noncompressible vessels
• Cerebrovascular disease
• Recent gastrointestinal or genitourinary bleeding
• Recent trauma
• Hypertension: systolic BP >/=180 mm Hg and/or diastolic BP >/=110 mm Hg
• High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
• Acute pericarditis
• Subacute bacterial endocarditis
• Hemostatic defects including those secondary to severe hepatic or renal disease
• Severe hepatic or renal dysfunction
• Pregnancy
• Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions
• Septic thrombophlebitis or occluded AV cannula at a seriously infected site
• Advanced age
• Patients currently receiving oral anticoagulants, e.g., warfarin sodium
• Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.

Source: [package insert]

Mass General Guidelines:
Arterial Thrombolysis:
* loading dose of 5 units
* 0.25 units/hour (low dose regimen) total dose
* 1 unit/hr (high dose regimen) total dose
* Heparin subtherapeutic dose of 100-150 units/hour. The dose of heparin is not altered on the basis of a PTT.
* Infusions are continued for a maximum of 48 hours.

Venous Thrombolysis:
* loading dose of 2 units
* 0.5-1 unit/hour (Total dose)
* Heparin at full therapeutic dose to maintain the PTT at more than 2 times control.
* Infusions are continued for up to 72 hours.
Disclaimer
The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material.  PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING THIS SITE. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.
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