Alteplase

U.S. BRAND NAMES — Activase®; Cathflo® Activase®

PHARMACOLOGIC CATEGORY
Thrombolytic Agent

DOSING: ADULTS
Coronary artery thrombi: I.V. Front loading dose (weight-based):
Patients >67 kg: Total dose: 100 mg over 1.5 hours; infuse 15 mg over 1-2 minutes. Infuse 50 mg over 30 minutes. Infuse remaining 35 mg of alteplase over the next hour. See "Note."
Patients 67 kg: Infuse 15 mg I.V. bolus over 1-2 minutes, then infuse 0.75 mg/kg (not to exceed 50 mg) over next 30 minutes, followed by 0.5 mg/kg over next 60 minutes (not to exceed 35 mg). See "Note."
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.

Acute pulmonary embolism: I.V.: 100 mg over 2 hours.

Acute ischemic stroke: I.V.: 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 I.V. 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>185 mm Hg systolic or >110 mm Hg diastolic); seizure at the onset of stroke; active internal bleeding; intracranial neoplasm; arteriovenous malformation or aneurysm; known bleeding diathesis including but not limited to: current use of anticoagulants or an INR >1.7, administration of heparin within 48 hours preceding the onset of stroke and an elevated aPTT at presentation, platelet count <100,000/mm3.>400 mg/dL, arterial puncture at a noncompressible site or lumbar puncture within 1 week, clinical presentation suggesting post-MI pericarditis, pregnancy, breast-feeding.

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Arrhythmias: Coronary thrombolysis may result in reperfusion arrhythmias. Bleeding: Doses >150 mg are associated with increased risk of intracranial hemorrhage; monitor all potential bleeding sites. If serious bleeding occurs, the infusion of alteplase and heparin should be stopped.

Disease-related concerns: Conditions that increase bleeding risk: For the following conditions, the risk of bleeding is higher with use of thrombolytics and should be weighed against the benefits of therapy: Recent (within 10 days) major surgery (eg, CABG, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels), cerebrovascular disease, recent gastrointestinal or genitourinary bleeding, recent trauma, hypertension (systolic BP >175 mm Hg and/or diastolic BP >110 mm Hg), high likelihood of left heart thrombus (eg, mitral stenosis with atrial fibrillation), acute pericarditis, subacute bacterial endocarditis, hemostatic defects including ones caused by severe renal or hepatic dysfunction, significant hepatic dysfunction, diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, septic thrombophlebitis or occluded AV cannula at seriously infected site and/or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of location. Myocardial infarct (MI): Appropriate use: Follow standard management for MI while infusing alteplase. Stroke: Appropriate use: Treatment of patients with acute ischemic stroke more than 3 hours after symptom onset is not recommended. Treatment of patients with minor neurological deficit or with rapidly improving symptoms is not recommended.

Concurrent drug therapy issues: Anticoagulants: Use with caution in patients receiving oral anticoagulants; increased risk of bleeding. Heparin: Concurrent heparin anticoagulation may contribute to bleeding.

Special populations: Elderly: Use with caution in patients with advanced age (eg, >75 years); increased risk of bleeding. Pregnancy: Use with caution in pregnancy; increased risk of bleeding.

Dosage form specific issues: Cathflo® Activase®: When used to restore catheter function, use Cathflo® cautiously in those patients with known or suspected catheter infections. Evaluate catheter for other causes of dysfunction before use. Avoid excessive pressure when instilling into catheter.

Other warnings/precautions: Administration: Intramuscular injections and nonessential handling of the patient should be avoided. Venipunctures should be performed carefully and only when necessary. If arterial puncture is necessary, use an upper extremity vessel that can be manually compressed.

DRUG INTERACTIONS
Aminocaproic acid (antifibrinolytic agent) may decrease effectiveness.

Drugs which affect platelet function (eg, NSAIDs, dipyridamole, ticlopidine, clopidogrel, IIb/IIIa antagonists) may potentiate the risk of hemorrhage; use with caution.

Heparin and aspirin: Use with aspirin and heparin may increase the risk of bleeding. However, aspirin and heparin were used concomitantly with alteplase in many patients in myocardial infarction or pulmonary embolism trials. This combination was prohibited in the NINDS tPA stroke trial.

Nitroglycerin may increase the hepatic clearance of alteplase, potentially reducing lytic activity (limited clinical information).

Warfarin or oral anticoagulants: Risk of bleeding may be increased during concurrent therapy.

ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, red clover, horse chestnut, garlic, green tea, ginseng, ginkgo (all have additional antiplatelet activity).

PREGNANCY RISK FACTOR — C (show table)

LACTATION — Excretion in breast milk unknown/use caution

MONITORING PARAMETERS
When using for central venous catheter clearance: Assess catheter function by attempting to aspirate blood.

When using for management of acute myocardial infarction: Assess for evidence of cardiac reperfusion through resolution of chest pain, resolution of baseline ECG changes, preserved left ventricular function, cardiac enzyme washout phenomenon, and/or the appearance of reperfusion arrhythmias; assess for bleeding potential through clinical evidence of GI bleeding, hematuria, gingival bleeding, fibrinogen levels, fibrinogen degradation products, prothrombin times, and partial thromboplastin times.

REFERENCE RANGE
Not routinely measured; literature supports therapeutic levels of 0.52-1.8 mcg/mL

Fibrinogen: 200-400 mg/dL

Activated partial thromboplastin time (aPTT): 22.5-38.7 seconds

Prothrombin time (PT): 10.9-12.2 seconds

TOXICOLOGY / OVERDOSE COMPREHENSIVE — Symptoms include increased incidence of intracranial bleeding.

CANADIAN BRAND NAMES — Activase® rt-PA; Cathflo® Activase®

INTERNATIONAL BRAND NAMES — Actilyse (AE, AR, AT, AU, BE, BF, BG, BH, BJ, BR, CH, CI, CL, CN, CO, CY, CZ, DE, DK, EE, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, HK, HU, ID, IN, IQ, IR, IT, JO, KE, KR, KW, LB, LR, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, NO, NZ, OM, PH, PL, PT, PY, QA, SA, SC, SD, SE, SG, SL, SN, SY, TH, TW, TZ, UG, UY, YE, ZA, ZM, ZW); Activacin (JP); Activase rt-PA (CA); Cathflo Activase (CA)

MECHANISM OF ACTION — Initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converts entrapped plasminogen to plasmin

PHARMACODYNAMICS / KINETICS
Duration: >50% present in plasma cleared ~5 minutes after infusion terminated, ~80% cleared within 10 minutes

Excretion: Clearance: Rapidly from circulating plasma (550-650 mL/minute), primarily hepatic; >50% present in plasma is cleared within 5 minutes after the infusion is terminated, ~80% cleared within 10 minutes