Thrombolytic Agents

alteplase (Activase ®, t-PA)	reteplase (Retavase ®)
Streptokinase	tenecteplase (TNKase ®)
Urokinase

alteplase (Activase ®, t-PA)

Acute MI: (>67kg): 15 mg IV bolus over 1-2 minutes, then 50 mg over 30 minutes, then 35 mg over next 60 minutes. (<67kg): 15 mg IV bolus, followed by 0.75 mg/kg (maximum 50mg) over 30 minutes, then 0.5 mg/kg (maximum 35mg) over the next 60 minutes. Note: Concurrently, begin heparin 60 units/kg bolus (maximum: 4000 units) followed by continuous infusion of 12 units/kg/hour (maximum: 1000 units/hour) and adjust to aPTT target of 1.5-2 times the upper limit of control. Infuse remaining 35 mg of alteplase over the next hour.

Acute PE: 100mg IV over 2 hours, then restart heparin when PTT < twice normal.

Acute ischemic stroke: Doses should be given within the first 3 hours of the onset of symptoms. Recommended total dose: 0.9 mg/kg (maximum dose should not exceed 90 mg) infused over 60 minutes. Load with 0.09 mg/kg (10% of the 0.9 mg/kg dose) as an IV bolus over 1 minute, followed by 0.81 mg/kg (90% of the 0.9 mg/kg dose) as a continuous infusion over 60 minutes. Heparin should not be started for 24 hours or more after starting alteplase for stroke.

Central venous catheter clearance: Intracatheter (Cathflo™ Activase® 1 mg/ml): Patients <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg/2 ml. Retain in catheter for 0.5-2 hours. May instill a second dose if catheter remains occluded. Patients >30 kg: 2 mg/2ml- retain in catheter for 0.5-2 hours - may instill a second dose if catheter remains occluded.

Acute peripheral arterial occlusive disease (unlabeled use): Intra-arterial: 0.02-0.1 mg/kg/hour for up to 36 hours. The most common indications for thrombolysis were peripheral arterial occlusion and venous thrombosis. Preparation: Continuous infusion of alteplase (50 mg of alteplase reconstituted in 50 mL of sterile water and diluted with 0.9% normal saline solution to a concentration of 0.1 to 0.2 mg/mL). Infusion rate: 0.5 to 2 mg/hr x 6 to 72 hours depending on location.

Supplied: 50 mg, 100 mg vial ( powder for reconstitution). Cathflo: 2 mg.

Vancouver General Hospital Protocols

RECONSTITUTION AND STABILITY : 50mg and 100mg powder stable at room temperature; 2mg powder stable in fridge. reconstitute each 2mg, 50mg or 100mg vial with 2.2mL, 50mL or 100mL sterile water for injection, respectively (diluent provided with 50mg and 100mg vials). DO NOT USE bacteriostatic water. To avoid foaming, direct the stream of water down the side of the vial. DO NOT SHAKE. Roll the vial in the palm of hands to mix. The reconstituted solution yields a final concentration of 1mg/mL. following reconstitution, unused solution may be stored in freezer (-20°C) for 6 months, at room temperature for up to 8 hours or under refrigeration for 24 hours. Minimum dilution in D5W 0.5mg/mL; dilution in NS may be < 0.5mg/mL; diluted solutions to these concentrations stable x 24 hours at room temperature.

ROUTES OF ADMINISTRATION
Intracannular dwell - 1mg/1mL concentration.
Intracannular infusion. Dilute 12.5mg in 500mL NS (=1mg/40mL). Alt: Arterial occlusion: 0.1 mg/mL in NS .
Hemodialysis Unit: dilute 2mg in 50mL NS; infuse over 2 hours.

DOSAGE
1) Myocardial infarction:
Total recommended dose should not exceed 100 mg IV administered as follows:
15 mg as a bolus dose over 2 minutes. immediately followed by 0.75 mg/kg (not exceeding 50 mg) as a continuous infusion over the first 30 minutes, then 0.50 mg/kg IV (not exceeding 35 mg) over the next 60 minutes. For Intracoronary Use: first 25 mg administered into coronary artery at rate of 1 mg/min; next 25 mg administered intravenously at rate of 5 mg/hr (i.e. over 5 hours)

2) Acute Ischemic Stroke: 0.9mg/kg to a maximum dose of 90mg given as follows: 10% of total dose given as a bolus over 2 minutes immediately followed by 90% of total dose given IV by continuous infusion over 60 minutes

3) Massive Pulmonary Embolism: 100 mg IV infusion over 2 hours; initiate heparin at end of alteplase infusion.

4) Lysis of Central Venous Catheter Occlusion: for lumen volumes < 1mL , instil 1mL (1mg) of 1mg/mL solution; for lumen volumes > 1mL, instil 2mL (2mg) of 1mg/mL solution. Dwell x 1 hour, then aspirate; may repeat x 1. For hemodialyis patients: instil 1mL of 1mg/1mL solution into lumen of catheter, then add NS to catheter volume + 0.2mL (e.g. if lumen volume is 2.2mL, instil 1mL altpelase and follow with 1.4mL NS); dwell x 1 hour then aspirate or leave in situ until next dialysis. CVC Partial Occlusion - 2 mg/50mL NS infused over 2 hours; monitor vital signs q1h during infusion. Note this dose of alteplase does not cause systemic thrombolysis

5) Infusion for Lysis of Acute Occlusion: 0.5 - 2.0mg/hour (usual 1mg/hour) intracannular x 6-72 hours.

6) Pleural Instillation: 4-6 mg (up to 0.1 mg/kg) in 30-100 mL NS instilled via chest tube; dwell 1-2 hours; may repeat daily until resolution of pleural fluid drainage (1-14 days)

reteplase (Retavase ®)

Use
Management of acute myocardial infarction (AMI); improvement of ventricular function; reduction of the incidence of CHF and the reduction of mortality following AMI

Mechanism of Action
Reteplase is a nonglycosylated form of tPA produced by recombinant DNA technology using E. coli ; it initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converts entrapped plasminogen to plasmin

Dosing:
Adults: 10 units I.V. over 2 minutes, followed by a second dose 30 minutes later of 10 units I.V. over 2 minutes. Withhold second dose if serious bleeding or anaphylaxis occurs.

Supplied:
Injection, powder for reconstitution [preservative free]: 10.4 units [equivalent to reteplase 18.1 mg; packaged with sterile water for injection]

Additional Info

Streptokinase:

Adults: Antibodies to streptokinase remain for at least 3-6 months after initial dose: Administration requires the use of an infusion pump. An intradermal skin test of 100 units has been suggested to predict allergic response to streptokinase. If a positive reaction is not seen after 15-20 minutes, a therapeutic dose may be administered.

Acute MI: 1.5 million units IV over 60 minutes. ( Administer as soon as possible after onset of symptoms. The greatest benefit in mortality reduction was observed when Streptokinase was administered within four hours, but statistically significant benefit has been reported up to 24 hours). Administration: Dilute two 750,000 unit vials of streptokinase with 5 mL dextrose 5% in water (D5W) each, gently swirl to dissolve. Add this dose of the 1.5 million units to 150 mL D5W. This should be infused over 60 minutes; an in-line filter 0.45 micron should be used. Monitor for the first few hours for signs of anaphylaxis or allergic reaction. Infusion should be slowed if blood pressure falls by 25 mm Hg or terminated if asthmatic symptoms appear. Following completion of streptokinase, initiate heparin, if directed, when aPTT returns to less than 2 times the upper limit of control; do not use a bolus, but initiate infusion adjusted to a target aPTT of 1.5-2 times the upper limit of control. If prolonged (>48 hours) heparin is required, infusion may be switched to subcutaneous therapy.

Acute pulmonary embolism (APE): 3 million unit dose over 24 hours. Administration: Dilute four 750,000 unit vials of streptokinase with 5 mL dextrose 5% in water (D5W) each, gently swirl to dissolve. Add this dose of 3 million units to 250 mL D5W, an in-line filter 0.45 micron should be used. Administer 250,000 units (23 mL) over 30 minutes followed by 100,000 units/hour (9 mL/hour) for 24 hours. Monitor for the first few hours for signs of anaphylaxis or allergic reaction. Infusion should be slowed if blood pressure is lowered by 25 mm Hg or if asthmatic symptoms appear. Begin heparin 1000 units/hour about 3-4 hours after completion of streptokinase infusion or when PTT is <100 seconds. Monitor PT, PTT, and fibrinogen levels during therapy.

Important note: Since human exposure to streptococci is common, antibodies to Streptokinase are prevalent. Thus, a loading dose of Streptokinase sufficient to neutralize these antibodies is required. A dose of 250,000 IU of Streptokinase infused into a peripheral vein over 30 minutes has been found appropriate in over 90% of patients. Furthermore, if the thrombin time or any other parameter of lysis after 4 hours of therapy is not significantly different from the normal control level, discontinue Streptokinase because excessive resistance is present.

Thromboses: 250,000 units to start, then 100,000 units/hour for 24-72 hours depending on location.

Cannula occlusion: 250,000 units into cannula, clamp for 2 hours, then aspirate contents and flush with normal saline; Not recommended.

tenecteplase (TNKase ®)

Treatment should be initiated as soon as possible after the onset of AMI symptoms. The recommended total dose should not exceed 50 mg and is based upon patient weight. A single bolus dose should be administered over 5 seconds based on patient weight.
Dose Information Table
Patient Wt (kg) TNKase (mg)   Volume (ml) over 5 seconds
< 60                            30mg                   6ml
60 to < 70                    35                       7
70 to < 80                    40                       8
80 to < 90                    45                       9
Over 90                       50                      10

Preparation: dilute 50mg vial with 10ml sterile water (packaged with diluent and syringe).

All patients received 150-325 mg of aspirin as soon as possible and then daily. Intravenous heparin was initiated as soon as possible and aPTT was maintained between 50-70 seconds. Do not shake when reconstituting. Slight foaming is normal and will dissipate if left standing for several minutes. The reconstituted solution is 5 mg/mL. Any unused solution should be discarded. Tenecteplase is incompatible with dextrose solutions. Dextrose-containing lines must be flushed with a saline solution before and after administration. Administer as a single I.V. bolus over 5 seconds.

Supplied: 50 mg vial ( powder for reconstitution).

Urokinase

Myocardial infarction: 6000 international units/minute infused into the occluded coronary artery for up to 2 hours (therapy should be continued until the artery is maximally opened, usually 15 to 30 minutes).

Pulmonary embolism: loading dose, 4400 international units/kg IV over 10 minutes (90 mL/hr), followed by continuous infusion, 4400 international units/kg/hr IV for 12 hours (15 mL/hr), flush line at end of infusion.

Occluded catheter: 5000 international units instilled into occluded catheter, up to 2 doses may be used. (attempt to aspirate blood after 5 minutes of dwell time, if successful, aspirate 4-5 mL of blood and flush gently with NS, if unsuccessful, repeat every 5 minutes, if catheter is not open in 30 minutes, allow to dwell 30-60 more minutes and repeat catheter clearance: if still unsuccessful, a second dose may be instilled.)

Reconstitute vial with 5 mL sterile water c/o preservatives - DO NOT shake.

Deep vein thrombosis (unlabeled use): I.V.: Loading: 4400 units/kg over 10 minutes, then 4400 units/kg/hour for 12 hours Adults: Acute pulmonary embolism: I.V.: Loading: 4400 units/kg over 10 minutes; maintenance: 4400 units/kg/hour for 12 hours. Following infusion, anticoagulation treatment is recommended to prevent recurrent thrombosis. Do not start anticoagulation until aPTT has decreased to less than twice the normal control value. If heparin is used, do not administer loading dose. Treatment should be followed with oral anticoagulants.

Myocardial infarction (unlabeled use): Intracoronary: 750,000 units over 2 hours (6000 units/minute over up to 2 hours)

Occluded I.V. catheters (unlabeled use): 5000 units in each lumen over 1-2 minutes, leave in lumen for 1-4 hours, then aspirate; may repeat with 10,000 units in each lumen if 5000 units fails to clear the catheter; do not infuse into the patient; volume to instill into catheter is equal to the volume of the catheter.
I.V. infusion: 200 units/kg/hour in each lumen for 12-48 hours at a rate of at least 20 ml/hour

Dialysis patients: 5000 units is administered in each lumen over 1-2 minutes; leave urokinase in lumen for 1-2 days, then aspirate

ADMINISTRATION — Solution may be filtered using a 0.22 or 0.45 micron filter during I.V. therapy. Administer using a pump which can deliver a total volume of 195 ml. The loading dose should be administered at 90 ml/hour over 10 minutes. The maintenance dose should be administered at 15 mL/hour over 12 hours. I.V. tubing should be flushed with NS or D5W to ensure total dose is administered.

Disclaimer

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David F. McAuley, Pharm.D., R.Ph. GlobalRPh Inc.

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