Alteplase

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Activase® may be confused with Cathflo® Activase®, TNKase®
Alteplase may be confused with Altace®
"tPA" abbreviation should not be used when writing orders for this medication; has been misread as TNKase (tenecteplase)

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication (I.V.) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

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

PHARMACOLOGIC CATEGORY
Thrombolytic Agent

DOSING: ADULTS
ST-elevation myocardial infarction (STEMI): I.V. (Activase®): 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: All patients should receive 162-325 mg of chewable nonenteric coated aspirin as soon as possible and then daily. Administer concurrently with 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 50-70 seconds (or 1.5-2 times the upper limit of control).

Acute pulmonary embolism: I.V. (Activase®): 100 mg over 2 hours.

Acute ischemic stroke: I.V. (Activase®): Within 3 hours of the onset of symptom onset (labeled use) or within 3-4.5 hours of symptom onset (unlabeled use; del Zoppo, 2009; Hacke, 2008): Note: Initiation of anticoagulants (eg, heparin) or antiplatelet agents (eg, aspirin) within 24 hours after starting alteplase is not recommended; however, initiation of aspirin between 24-48 hours after stroke onset is recommended (Adams, 2007). Initiation of SubQ heparin (≤ 10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3-4.5 hour window trial did not increase incidence of intracerebral hemorrhage (Hacke, 2008).
Recommended total dose: 0.9 mg/kg (maximum total dose: 90 mg)
Patients ≤ 100 kg: Load with 0.09 mg/kg (10% of 0.9 mg/kg dose) as an I.V. bolus over 1 minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion over 60 minutes.
Patients >100 kg: Load with 9 mg (10% of 90 mg) as an I.V. bolus over 1 minute, followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes.

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®: ST-elevation 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

Activase®: Acute ischemic stroke: Bolus dose (10% of total dose) may be prepared by one of three methods:
1) Removal of the appropriate volume from reconstituted solution (1 mg/mL)
2) Removal of the appropriate volume from a port on the infusion line after priming
3) Programming an infusion pump to deliver the appropriate volume at the initiation of infusion

Note: Remaining dose for STEMI, AIS, or total dose for acute pulmonary embolism may be administered as follows: Any quantity of drug not to be administered to the patient must be removed from vial(s) prior to administration of remaining dose.
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.

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 ST-elevation myocardial infarction (STEMI) for the lysis of thrombi in coronary arteries; management of acute ischemic stroke (AIS); management of acute pulmonary embolism

Recommended criteria for treatment:
STEMI: Chest pain ≥ 20 minutes duration, onset of chest pain within 12 hours of treatment (or within prior 12-24 hours in patients with continuing ischemic symptoms), and ST-segment elevation >0.1 mV in at least two contiguous precordial leads or two adjacent limb leads on ECG or new or presumably new left bundle branch block (LBBB)
AIS: Onset of stroke symptoms within 3 hours of treatment
Acute pulmonary embolism: 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 ischemic stroke presenting 3-4.5 hours after symptom onset; 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 STEMI: 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 STEMI 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; suspected aortic dissection

Treatment of acute ischemic stroke: Evidence of intracranial hemorrhage or suspicion of subarachnoid hemorrhage on pretreatment evaluation; intracranial or intraspinal surgery within 3 months; stroke or serious head injury within 3 months; 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; multilobar cerebral infarction (hypodensity >1/3 cerebral hemisphere; Adams, 2007); clinical presentation suggesting post-MI pericarditis; known bleeding diathesis including but not limited to current use of oral anticoagulants producing an INR >1.7, an INR >1.7, administration of heparin within 48 hours preceding the onset of stroke with an elevated aPTT at presentation, platelet count <100,000/mm3.
Additional exclusion criteria within clinical trials:
Presentation <3>400 mg/dL, and arterial puncture at a noncompressible site or lumbar puncture within 1 week.
Presentation 3-4.5 hours after initial symptoms (ECASS-III; Hacke, 2008): Age >80 years, time of symptom onset unknown, rapidly improving or minor symptoms, current use of anticoagulants regardless of INR, glucose level <50>400 mg/dL, aggressive intravenous treatment required to lower blood pressure, major surgery or severe trauma within 3 months, baseline National Institutes of Health Stroke Scale (NIHSS) score >25, and history of both stroke and diabetes.

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Arrhythmias: Coronary thrombolysis may result in reperfusion arrhythmias. Bleeding: Do not use doses >150 mg; associated with increased risk of intracranial hemorrhage. The total dose should not exceed 90 mg for acute ischemic stroke or 100 mg for acute myocardial infarction or pulmonary embolism. 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, pregnancy, previous puncture of noncompressible vessels), prolonged CPR with evidence of thoracic trauma, lumbar puncture within 1 week, 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. ST-elevation myocardial infarction (STEMI): Appropriate use: Follow standard management for STEMI while infusing alteplase. Stroke: Appropriate use: Patients who present within 3 hours of stroke symptom onset should be treated with alteplase unless contraindications exist. A longer time window (3-4.5 hours after symptom onset) has now been formally evaluated and shown to be safe and efficacious for select individuals (del Zoppo, 2009; Hacke, 2008).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. In the treatment of acute ischemic stroke, the current use of oral anticoagulants producing an INR >1.7 is a contraindication. Aspirin: In the treatment of acute ischemic stroke, avoid aspirin for 24 hours following administration of alteplase; administration within 24 hours increases the risk of hemorrhagic transformation. Heparin: Concurrent heparin anticoagulation may contribute to bleeding. In the treatment of acute ischemic stroke, concurrent use of anticoagulants was not permitted during the initial 24 hours of the <3 hour window trial (NINDS, 1995). Initiation of SubQ heparin (≤ 10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3-4.5 hour window trial was permitted and did not increase the incidence of intracerebral hemorrhage (Hacke, 2008).

Special populations: Elderly: Use with caution in patients with advanced age (eg, >75 years); increased risk of bleeding. Acute ischemic stroke (within 3-4.5 hours after symptom onset): Patients >80 years were excluded from the clinical trial (Hacke, 2008). 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
Anticoagulants: Thrombolytic Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Antiplatelet Agents: May enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy

Aprotinin: May diminish the therapeutic effect of Thrombolytic Agents. Risk D: Consider therapy modification

Drotrecogin Alfa: Thrombolytic Agents may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Risk D: Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Thrombolytic Agents. Bleeding may occur. Risk D: Consider therapy modification

Nitroglycerin: May decrease the serum concentration of Alteplase. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy

Salicylates: May enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor 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)

PREGNANCY IMPLICATIONS — Teratogenic effects were not observed in animal studies. There are no adequate and well-controlled studies in pregnant women. The risk of bleeding may be increased in pregnant women. Use during pregnancy is limited; administer to pregnant women only if the potential benefits justify the risk to the fetus.

LACTATION — Excretion in breast milk unknown/use caution

MONITORING PARAMETERS
Acute ischemic stroke: In addition to monitoring for bleeding complications, the 2007 AHA/ASA Guidelines for the early management of acute ischemic stroke recommends the following:
Perform neurological assessments every 15 minutes during infusion and every 30 minutes thereafter for the next 6 hours, then hourly until 24 hours after treatment.
If severe headache, acute hypertension, nausea, or vomiting occurs, discontinue the infusion and obtain emergency CT scan.
Measure BP every 15 minutes for the first 2 hours then every 30 minutes for the next 6 hours, then hourly until 24 hours after initiation of alteplase. Increase frequency if a systolic BP is ≥ 180 mm Hg or if a diastolic BP is ≥ 105 mm Hg; administer antihypertensive medications to maintain BP at or below these levels.
Obtain a follow-up CT scan at 24 hours before starting anticoagulants or antiplatelet agents.

Central venous catheter clearance: Assess catheter function by attempting to aspirate blood.

ST-elevation MI: 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

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

INTERNATIONAL BRAND NAMES — Actilyse (AE, AR, AT, AU, BD, 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, HN, HU, ID, IE, IL, IN, IQ, IR, IT, JO, JP, KE, KP, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, NO, OM, PH, PK, PL, PT, PY, QA, SA, SC, SD, SE, SG, SL, SN, SY, TH, TN, TW, TZ, UG, UY, VE, YE, ZA, ZM, ZW); Activacin (JP)

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