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 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 (2 mL); 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 Advisory Panel to the Society for Cardiovascular and Interventional Radiology on Thrombolytic Therapy recommendation: 2 mg/hour and subtherapeutic heparin (aPTT <1.5 times baseline)
DOSING: PEDIATRIC — Central venous catheter clearance: Intracatheter: 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
(For additional information see "Alteplase: Pediatric drug information")
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution, recombinant: Activase®: 50 mg [29 million int. units; contains polysorbate 80; packaged with diluent]; 100 mg [58 million int. units; contains polysorbate 80; packaged with diluent and transfer device] Cathflo® Activase®: 2 mg [contains polysorbate 80]
DOSAGE FORMS: CONCISE Injection, powder for reconstitution, recombinant: Activase®: 50 mg [29 million int. units]; 100 mg [58 million int. units] Cathflo® Activase®: 2 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION Activase®: Acute MI: Accelerated infusion: Bolus dose may be prepared by one of three methods: 1) removal of 15 mL reconstituted (1 mg/mL) solution from vial 2) removal of 15 mL from a port on the infusion line after priming 3) programming an infusion pump to deliver a 15 mL bolus at the initiation of infusion Remaining dose may be administered as follows: 50 mg vial: Either PVC bag or glass vial and infusion set 100 mg vial: Insert spike end of the infusion set through the same puncture site created by transfer device and infuse from vial If further dilution is desired, may be diluted in equal volume of 0.9% sodium chloride or D5W to yield a final concentration of 0.5 mg/mL AD
Cathflo® Activase®: Intracatheter: Instill dose into occluded catheter. Do not force solution into catheter. After a 30-minute dwell time, assess catheter function by attempting to aspirate blood. If catheter is functional, aspirate 4-5 mL of blood in patients 10 kg or 3 mL in patients <10 kg to remove Cathflo® Activase® and residual clots. Gently irrigate the catheter with NS. If catheter remains nonfunctional, let Cathflo® Activase® dwell for another 90 minutes (total dwell time: 120 minutes) and reassess function. If catheter function is not restored, a second dose may be instilled.
COMPATIBILITY — Stable in NS, sterile water for injection; incompatible with bacteriostatic water; variable stability (consult detailed reference) in D5W.
Y-site administration: Compatible: Lidocaine, metoprolol, propranolol. Incompatible: Dobutamine, dopamine, heparin, nitroglycerin.
Compatibility when admixed: Compatible: Lidocaine, morphine, nitroglycerin. Incompatible: Dobutamine, dopamine, heparin.
USE — Management of acute myocardial infarction for the lysis of thrombi in coronary arteries; management of acute ischemic stroke
Acute myocardial infarction (AMI): Chest pain 20 minutes, 12-24 hours; S-T elevation 0.1 mV in at least two ECG leads
Acute pulmonary embolism (APE): Age 75 years: Documented massive pulmonary embolism by pulmonary angiography or echocardiography or high probability lung scan with clinical shock
Cathflo® Activase®: Restoration of central venous catheter function
USE - UNLABELED / INVESTIGATIONAL — Acute peripheral arterial occlusive disease
ADVERSE REACTIONS SIGNIFICANT — As with all drugs which may affect hemostasis, bleeding is the major adverse effect associated with alteplase. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the dosage administered, concurrent use of multiple agents which alter hemostasis, and patient predisposition. Rapid lysis of coronary artery thrombi by thrombolytic agents may be associated with reperfusion-related atrial and/or ventricular arrhythmia. Note: Lowest rate of bleeding complications expected with dose used to restore catheter function.
1% to 10%: Cardiovascular: Hypotension Central nervous system: Fever Dermatologic: Bruising (1%) Gastrointestinal: GI hemorrhage (5%), nausea, vomiting Genitourinary: GU hemorrhage (4%) Hematologic: Bleeding (0.5% major, 7% minor: GUSTO trial) Local: Bleeding at catheter puncture site (15.3%, accelerated administration)
<1% (Limited to important or life-threatening): Allergic reactions: Anaphylaxis, anaphylactoid reactions, laryngeal edema, rash, and urticaria (<0.02%); epistaxis; gingival hemorrhage; intracranial hemorrhage (0.4% to 0.87% when dose is 100 mg); pericardial hemorrhage; retroperitoneal hemorrhage
Additional cardiovascular events associated with use in MI: AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia/infarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema, asystole, ventricular tachycardia, bradycardia, ruptured intracranial AV malformation, seizure, hemorrhagic bursitis, cholesterol crystal embolization
Additional events associated with use in pulmonary embolism: Pulmonary re-embolization, pulmonary edema, pleural effusion, thromboembolism
Additional events associated with use in stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke
CONTRAINDICATIONS — Hypersensitivity to alteplase or any component of the formulation
Treatment of acute MI or PE: Active internal bleeding; history of CVA; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm; arteriovenous malformation or aneurysm; known bleeding diathesis; severe uncontrolled hypertension
Treatment of acute ischemic stroke: Evidence of intracranial hemorrhage or suspicion of subarachnoid hemorrhage on pretreatment evaluation; recent (within 3 months) intracranial or intraspinal surgery; prolonged external cardiac massage; suspected aortic dissection; serious head trauma or previous stroke; history of intracranial hemorrhage; uncontrolled hypertension at time of treatment (eg, >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.
Other exclusion criteria (NINDS recombinant tPA study): Stroke or serious head injury within 3 months, major surgery or serious trauma within 2 weeks, GI or urinary tract hemorrhage within 3 weeks, aggressive treatment required to lower blood pressure, glucose level <50>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