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Alteplase

Class: Thrombolytic Agents
Brands: Activase, Cathflo Activase

Medically reviewed on Oct 23, 2017

Introduction

Thrombolytic agent;1 2 46 biosynthetic (recombinant DNA origin) form of human tissue-type plasminogen activator (t-PA).4 5 8 11 12 13 14 15 19 21 31 35 36 46 62 67

Uses for Alteplase

Acute MI

Used for reperfusion therapy in patients with acute MI,1 2 34 37 38 41 42 43 46 47 48 65 75 80 83 141 193 527 in conjunction with appropriate anticoagulant (e.g., heparin) and antiplatelet (e.g., aspirin and clopidogrel) therapies.1 2 14 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 50 57 59 65 68 69 72 75 78 79 80 83 84 85 117 141 154 155 163 168 193 194 226 527

Current standard of care in patients with ST-segment-elevation MI (STEMI) is timely reperfusion (with primary PCI or thrombolytic therapy).527 994 The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline states that reperfusion therapy should be administered to all eligible patients with STEMI and onset of ischemic symptoms within the previous 12 hours.527 994 Select appropriate reperfusion method based on a risk-benefit analysis, considering the time from onset of MI symptoms, patient's clinical and hemodynamic status, comorbidities (e.g., severe heart failure), bleeding risk, contraindications, and availability (and timeliness) of PCI.527

Primary PCI is preferred when it can be performed in a timely manner.527 994 Thrombolytic therapy is recommended when it is anticipated that PCI cannot be performed within 120 minutes of first medical contact.527

Benefits of thrombolytic therapy in patients with STEMI are well established;527 resulting reperfusion can limit infarct size,1 48 193 improve ventricular function,1 2 4 38 42 46 47 48 50 69 193 and reduce the incidence of heart failure1 2 38 and death.1 42 46 193 194 226

Clinical benefit diminishes as the time period from symptom onset to initiation of therapy increases.42 51 52 67 68 193 205 527 Administer as soon as possible after acute MI.1 2 4 14 31 32 33 34 35 36 37 38 39 40 41 42 43 46 47 48 222 ACCF and AHA recommend administration within 30 minutes of hospital arrival.527

Pulmonary Embolism

Lysis of acute pulmonary emboli involving obstruction of blood flow to a lobe or multiple segments of the lungs.1 15 46 86 87 88 89 90 91 92 93 269 270 271 272 273 274 275 276

Lysis of acute pulmonary emboli accompanied by unstable hemodynamics (i.e., when BP cannot be maintained without supportive measures).1 15 46 86 87 88 89 90 91 92 93 269 270 271 272 273 274 275 276

The American College of Chest Physicians (ACCP) generally recommends against the use of systemic thrombolytic therapy in most patients with acute PE; however, in patients with acute PE associated with hypotension (e.g., SBP <90 mm Hg), thrombolytic therapy may provide some benefit in terms of mortality reduction and is suggested as a possible treatment in patients without high risk of bleeding.1005

Acute Ischemic Stroke

Management of acute ischemic stroke to improve neurologic recovery and reduce the incidence of disability.1 2 3 4 5 6 322 357 358 378 379 387 388 389 390 391 392 393 394 395 396 397 1009

Should be initiated within 3–4.5 hours following the onset of symptoms of acute ischemic stroke and only after intracranial hemorrhage has been excluded by cranial CT scan or other diagnostic imaging method sensitive for the presence of hemorrhage.1 322 357 358 392 394 395 396 1009 However, because benefit from thrombolytic therapy decreases substantially with time, such therapy should be administered as soon as possible following onset of stroke symptoms to obtain optimal benefit; experts recommend a “door-to-needle” time (i.e., from arrival at the treating facility until injection of alteplase) of no more than 1 hour.387 388 389 390 392 393 396 398

Safety of alteplase treatment administered more than 4.5 hours after symptom onset, in dosages higher than 0.9 mg/kg and without careful blood-pressure management, not established;1 2 322 357 394 395 1009 some data389 suggest increased mortality with alteplase administration more than 4.5 hours following onset of stroke symptoms.389 390

Use of thrombolytic therapy not recommended by American Stroke Association (ASA) and other authorities in patients with major early ischemic changes on baseline CT scan (defined as clearly identifiable hypodensity involving more than one-third of the middle cerebral artery territory).358

Use of thrombolytic therapy not recommended in patients with minor neurologic deficit or with rapidly improving symptoms.1

Arterial Thrombosis and Embolism

Intra-arterial thrombolytic therapy for lysis of arterial occlusions in peripheral vessels and bypass grafts.94 95 96 97 98

ACCP suggests the use of intra-arterial thrombolytic therapy in patients with acute limb ischemia due to arterial emboli or thrombosis; however, surgical reperfusion is preferred over thrombolytic therapy.1011 If thrombolytic therapy is used, ACCP suggests that a recombinant tissue plasminogen activator (e.g., alteplase) or urokinase (no longer commercially available in the US) is preferred.1011

Occluded IV Catheters

Restoration of patency to central venous catheters obstructed by a thrombus (assessed by the ability to withdraw blood).325 1013

Consider causes of catheter dysfunction other than thrombus formation (e.g., catheter malposition, mechanical failure, constriction by a suture, lipid deposits, drug precipitates) before use.325

Alteplase Dosage and Administration

General

  • Institute therapy as soon as possible after acute MI.1 2 14 31 32 33 34 35 36 37 38 39 40 41 42 43 46 47 48 (See Acute MI under Uses.)

  • Initiate therapy for acute ischemic stroke within 3–4.5 hours of symptom onset.1 322 357 358 392 394 395 396 1009 Prior to administration, exclude intracranial hemorrhage by cranial CT scan or other sensitive diagnostic imaging method.1 322 May initiate therapy prior to the availability of coagulation results in patients without recent anticoagulant therapy (e.g., oral anticoagulants, heparin).1 Discontinue infusion if pretreatment coagulation results are abnormal (e.g., INR >1.7, PT >15 seconds, elevated aPTT).1

Administration

Administer by IV infusion, preferably via a controlled-infusion device2 using separate IV tubing (Activase).1 2

Administer by intracatheter instillation into occluded central venous catheters (Cathflo Activase).1 2 325

Also has been administered by intracoronary injection,30 221 selective intra-arterial infusion,89 90 102 103 104 and intraocularly via intracameral injection104 in a limited number of patients.

IV Administration

For solution and drug compatibility information, see Stability: Compatibility.

For coronary artery thrombosis and MI, administer by IV infusion over 3 hours or as an “accelerated” infusion over 1.5 hours.1 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 47 48 50 57 75 84 85 117 141 154 155 163 188 193 210 Some experts consider the accelerated infusion regimen the preferred method of administration.527

Reconstitution

Reconstitute vial containing 50 mg of alteplase by adding 50 mL of sterile water for injection without preservatives to provide a concentration of 1 mg/mL.1 Use a large-bore (e.g., 18-gauge) needle and direct diluent into the lyophilized cake of powder.1 2 Do not use diluents other than sterile water for injection without preservatives.1 2

Reconstitute vial containing 100 mg of alteplase with 100 mL of sterile water for injection without preservatives using supplied transfer device to provide a concentration of 1 mg/mL.1

Slight foaming is not unusual during reconstitution.1 Leave vial undisturbed for several minutes after addition of the diluent to allow dissipation of any large bubbles.1

Dilution

Administer as reconstituted (1 mg/mL) or dilute further just prior to administration to a concentration of approximately 0.5 mg/mL using 0.9% sodium chloride injection or 5% dextrose injection.1 2 More dilute solutions should not be used; drug may precipitate at concentrations of <0.5 mg/mL.221 Do not use other infusion solutions (e.g., sterile water for injection without preservatives, preservative-containing solutions).1 2 Mix solution with gentle swirling and/or slow inversion of the infusion container; avoid excessive agitation.1 2

Use reconstituted or diluted solutions within 8 hours.1 Discard any unused solutions.1

Administration into Occluded Central Venous Catheters

For clearing occluded central venous catheters, administer into occluded catheter.325

Reconstitution

Reconstitute solution for IV catheter clearance with 2.2 mL of sterile water for injection according to the manufacturer’s directions to provide a solution containing 1 mg/mL.325 Do not use bacteriostatic water for injection as a diluent.325

Slight foaming is not unusual during reconstitution.325 Leave vial undisturbed for several minutes after addition of diluent to allow dissipation of large bubbles.325

Dosage

Expressed in mg, but also may be expressed in international units (IU); each mg is equivalent to 580,000 units.1 2

Pediatric Patients

Occluded Central Venous IV Catheters
Intracatheter injection

Patients weighing <30 kg: 110% of the lumen volume of the catheter, with dosage not >2 mg (2 mL).325 Assess catheter function after at least 30 minutes by attempting to aspirate blood.325 If necessary, repeat aspiration attempt after 120 minutes of dwell time.325 Administer a second injection (110% of lumen volume, not >2 mg [2 mL]) in resistant cases;325 ACCP suggests a second dose of alteplase after 30 minutes of dwell time if the catheter remains occluded.1013 When patency is restored, aspirate 4–5 mL of blood in patients weighing ≥10 kg or 3 mL of blood in patients weighing <10 kg to remove all drug and clot residual.325 Irrigate catheter gently with 0.9% sodium chloride injection.325 If catheter patency not successfully established after 2 doses of alteplase, ACCP suggests radiologic imaging to rule out a catheter-related thrombus.1013

Patients weighing ≥30 kg: 2 mg (2 mL) into occluded catheter.325 Assess catheter function after at least 30 minutes by attempting to aspirate blood.325 If necessary, repeat aspiration attempt after 120 minutes of dwell time.325 Administer a second 2-mg injection (for a total of 4 mg) in resistant cases.325 ACCP suggests a second dose of alteplase after 30 minutes of dwell time if the catheter remains occluded.1013 When patency is restored, aspirate 4–5 mL of blood to remove all drug and clot residual.325 Irrigate catheter gently with 0.9% sodium chloride injection.325 If catheter patency not successfully established after 2 doses of alteplase, ACCP suggests radiologic imaging to rule out a catheter-related thrombus.1013

Adults

Acute MI
3-Hour Infusion
IV

Infuse total of 100 mg (58 million IU) over 3 hours.1 2 Initially, infuse 60 mg (34.8 million IU) during the first hour;1 2 6–10 mg of this dose is rapidly infused over 1–2 minutes.1 2 Subsequently, infuse 20 mg (11.6 million IU) per hour for the next 2 hours.1 2

In adults weighing <65 kg (lean or actual body weight, whichever is less), infuse 1.25 mg/kg over 3 hours.1 221 Initially, 0.75 mg/kg during the first hour; 0.045–0.075 mg/kg of this dose is rapidly infused over 1–2 minutes.199 221 Subsequently, infuse 0.25 mg/kg per hour for the next 2 hours.199 221

Accelerated Infusion
IV

In adults weighing >67 kg, initially, infuse total dose of 100 mg.1 7 Initially, inject 15 mg rapidly over 1–2 minutes,1 7 followed by 50 mg over the next 30 minutes, then 35 mg over the next hour.1

Alternatively, in patients weighing ≤67 kg, inject 15 mg rapidly over 1–2 minutes,1 7 followed by 0.75 mg/kg (up to 50 mg) over the next 30 minutes, then 0.5 mg/kg (up to 35 mg) over the next hour.1

Pulmonary Embolism
IV

100 mg (58 million IU) infused over 2 hours.1 91 271 273 Institute or reinstitute heparin therapy near the end of or immediately following alteplase infusion when aPTT or thrombin time returns to twice the normal value or less.1

Acute Ischemic Stroke
IV

0.9 mg/kg (up to 90 mg) infused over 1 hour.1 357 Initially, administer 10% of the dose rapidly over 1 minute.1 Do not exceed dose of 0.9 mg/kg (maximum 90 mg).1

Occluded Central Venous IV Catheters
Intracatheter injection

2 mg (2 mL) into occluded catheter in patients weighing ≥30 kg; allow to dwell for at least 30 minutes.325 Assess catheter function after 30 minutes by attempting to aspirate blood.325 If necessary, repeat aspiration attempt after 120 minutes of dwell time.325 Administer a second 2-mg injection (for a total of 4 mg) in resistant cases.325 ACCP suggests a second dose of alteplase after 30 minutes of dwell time if the catheter remains occluded.1013

When patency is restored, aspirate 4–5 mL of blood to remove all drug and clot residual.325 Irrigate catheter gently with 0.9% sodium chloride injection.325

If catheter patency is not successfully established after 2 doses of alteplase, ACCP suggests radiologic imaging to rule out a catheter-related thrombus.1013

Arterial Thrombosis and Embolism
Intra-arterial

0.05–0.1 mg/kg per hour for 1–8 hours for lysis of arterial occlusion in a peripheral vessel or bypass graft.94 95 96 97 Even lower dosages (e.g., 0.02 mg/kg per hour over 1–7 hours) may be effective.211

Prescribing Limits

Pediatric Patients

Occluded Central Venous IV Catheters
Intracatheter Injection

Maximum 2 mg per each attempt at clearing an occluded catheter, for a total dosage of 4 mg (2 courses).325

Adults

Coronary Artery Thrombosis and MI
IV

Maximum 100 mg.1 150 mg dose not recommended because of possible increased incidence of intracranial bleeding.1

Acute Ischemic Stroke
IV

Maximum 0.9 mg/kg (up to 90 mg) total dose.1

Occluded Central Venous IV Catheters
Intracatheter Injection

Maximum 2 mg per each attempt at clearing an occluded catheter, for a total dosage of 4 mg (2 courses).325

Cautions for Alteplase

Contraindications

    Acute MI or PE
  • Active internal bleeding.1 2

  • History of cerebrovascular accident or intracranial hemorrhage.1 2

  • Intracranial neoplasm.1 2

  • Aneurysm.1 2

  • Recent intracranial or intraspinal surgery or trauma.1 2

  • Known bleeding diathesis.1 2 154

  • Arteriovenous malformation.1 2 154

  • Severe uncontrolled hypertension.1 2 154

  • Suspected aortic dissection.1 2 154

    Acute Ischemic Stroke
  • Evidence of active internal bleeding, intracranial hemorrhage on pretreatment evaluation, suspicion of subarachnoid hemorrhage, history of intracranial hemorrhage, or recent (within 3 weeks) GI or urinary tract hemorrhage.1 322 358

  • Known bleeding diathesis.1 322 358

  • Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or recent previous stroke.1 322 358

  • Uncontrolled hypertension at time of treatment (e.g., SBP or DBP >185 or 110 mm Hg, respectively) or hypertension requiring aggressive treatment.1 322 358

  • Arteriovenous malformation or aneurysm.1 322 358

  • Seizure at onset of stroke.1 322 358

  • Intracranial neoplasm.1 322 358

Warnings/Precautions

Warnings

Effects on Hemostasis

Routine monitoring of hemostatic indices (e.g., fibrinogen concentrations, thrombin times) generally not recommended during therapy for acute MI.15 221 222 However, such monitoring is recommended for patients who exhibit bleeding.222

Possible bleeding and hemorrhagic complications,1 14 43 44 62 145 146 154 155 156 including intracranial hemorrhage and other major bleeding complications.141 222 May be more common in geriatric patients62 154 156 and those with a history of cerebrovascular accident or severe or poorly controlled hypertension.141 222

Weigh increased risks of therapy against anticipated benefits in patients with recent major surgery (e.g., coronary artery bypass), cerebrovascular disease, obstetric delivery, organ biopsy, previous puncture of noncompressible vessels, hypertension (SBP ≥175 mm Hg and/or DBP ≥110 mm Hg);1 2 322 high likelihood of hemostatic defects (e.g., secondary to severe hepatic or renal disease), internal (e.g., GI or GU) bleeding, or recent (within 2–4 weeks) trauma.1 2 222 Also, weigh risks against benefits of therapy in patients with diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions.1 2 Weigh risks against benefits in patients receiving concurrent oral anticoagulant therapy (e.g., warfarin).1 2 Weigh risks against benefits in patients with any condition in which bleeding constitutes a substantial hazard or would be particularly difficult to manage because of its location.1 2

Initiate therapy only after careful screening for contraindications (e.g., previous neurologic events, severe hypertension, and potential bleeding sites).142 244

Minimize risk of bleeding by carefully selecting patients and monitoring all potential bleeding sites (e.g., sites of all venous cutdowns, arterial and venous punctures, needle punctures).1 14 15 44 46 154 Avoid IM injections and nonessential handling of patient.1 46 Perform invasive venous procedures carefully and as infrequently as possible.1 46 If bleeding from the site of an invasive procedure or other trauma is not serious, continue therapy and closely observe the patient;221 222 initiate local measures (e.g., application of pressure) immediately.1 Avoid arterial and venous invasive procedures in areas inaccessible to manual compression (e.g., internal jugular or subclavian punctures) before and during therapy.1 221 222 Use of an artery in an upper extremity (e.g., radial or brachial) is preferable if arterial puncture is essential.1 46 222 Apply pressure to the puncture site for ≥30 minutes, followed by a pressure dressing and frequent inspection of the puncture site for bleeding.1 155

Possible severe and fatal spontaneous bleeding (e.g., cerebral,1 34 37 42 43 47 48 retroperitoneal,1 37 44 47 GU,1 31 41 44 47 respiratory tract,1 GI bleeding).1 33 36 39 41 43 44 47 48 154 Less severe spontaneous bleeding (e.g., superficial hematoma or ecchymoses,1 40 41 48 hematuria,41 43 hemoptysis,41 43 epistaxis,1 and gingival bleeding)1 41 43 also may occur.40 41

If serious spontaneous bleeding occurs, immediately discontinue alteplase therapy1 14 and initiate appropriate hemostatic therapy as needed.14 15 221 222 If serious bleeding at a critical location (e.g., intracranial, GI, retroperitoneal, pericardial) occurs with intracatheter instillation of alteplase, discontinue therapy immediately and withdraw the drug from the catheter.325

Extravasation during IV infusion may cause ecchymosis and/or inflammation.1 Terminate infusion at that IV site and apply local therapy.1

Cardiovascular Effects

Possible fatal cardiogenic shock, heart failure, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, hypotension, pulmonary edema, thromboembolism, or recurrent thromboembolic events.1

Weigh risks against anticipated benefits of therapy in patients with a high likelihood of left heart thrombus (e.g., mitral stenosis with atrial fibrillation, profound left ventricular dyskinesia),1 2 196 acute pericarditis,1 2 198 subacute bacterial endocarditis, septic thrombophlebitis, or an occluded arteriovenous cannula at a seriously infected site.1 2 222

Possible coronary artery reocclusion.4 14 31 34 35 37 39 40 41 60 74 208 Reocclusion rate greater with standard than with accelerated infusion.316 Reduce incidence of reocclusion through concomitant anticoagulation (e.g., heparin and/or oral anticoagulants)1 2 30 31 32 33 34 35 36 37 38 39 40 41 42 47 and/or platelet-aggregation inhibitor (e.g., aspirin, dipyridamole) therapy,1 37 38 39 40 41 43 193 prolonged infusion of the thrombolytic agent, or mechanical or surgical revascularization procedures.4 14 35 37 38 62 63 177

Possible thromboembolism or recurrent thromboembolic events, pleural effusion, hypotension, pulmonary edema, or fever.1 Confirm diagnosis objectively using pulmonary angiography or a noninvasive procedure (e.g., lung scanning).1 277 Potential risk of re-embolization resulting from lysis of deep venous thrombi.1 May not be adequate therapy for underlying DVT.1

Potential new embolic episodes, including those involving cerebral vessels.196 221 222 Avoid therapy in patients with arterial emboli originating from the left side of the heart (e.g., mitral stenosis accompanied by atrial fibrillation, left ventricular thrombi).196 221 222

Cerebrovascular Effects

Possible risk of stroke in patients with acute MI who are at low risk for cardiovascular death; risk may offset the survival benefit of thrombolytic therapy.1

Weigh increased risks of therapy associated with cerebrovascular disease against anticipated benefits of therapy.1 2 222 322

Manufacturer suggests weighing risks of intracranial hemorrhage against anticipated benefits of therapy in patients with severe neurologic deficit (e.g., NIHSS score >22) on pretreatment evaluation of acute ischemic stroke1 357 and in patients with major early infarct signs on CT scan (e.g., substantial edema, mass effect, midline shift).1 However, AHA and ASA state that thrombolytic therapy almost always should not be administered to patients with major early infarct signs.358

In patients with acute ischemic stroke, administer in facilities that can provide appropriate evaluation and management of intracranial hemorrhage.1 Incidence of intracranial hemorrhage and benefits of therapy unknown in patients treated >3 hours after the onset of symptoms; use not recommended in such patients and in patients with symptoms of unknown duration.1 322 358 Frequently monitor and control BP during and following administration.1 357 Safety of administration without careful BP management not established.1 2 322

Cholesterol Embolization

Possibly fatal cholesterol crystal embolization associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.1 Clinical features of cholesterol embolism include livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits,1 267 hypertension, pancreatitis, MI, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.1 267

Arrhythmias

Possible reperfusion-related atrial1 32 162 163 164 166 and/or ventricular1 67 162 163 164 165 187 arrhythmias (e.g., accelerated idioventricular rhythm,67 155 162 163 187 VPCs,67 162 atrial fibrillation,163 165 atrial premature complexes,166 junctional rhythm,163 VT,162 sinus bradycardia).32 67 155 162 163 164 Such arrhythmias are usually transient.187

Careful monitoring recommended.1 164 Have appropriate antiarrhythmic therapy available during and immediately after administration.1 164

Hepatic Effects

Weigh anticipated benefits of therapy against increased risks associated with substantial liver dysfunction.1 2 222

Sensitivity Reactions

Hypersensitivity Reactions

Allergic-type reactions (e.g., anaphylactoid reaction, laryngeal edema, orolingual edema, rash, urticaria) occur rarely.1 2 145 Many of the patients experiencing orolingual edema were receiving concomitant ACE inhibitors.1

Monitor patients during and several hours following infusion for signs of orolingual angioedema.1 Administer appropriate therapy (e.g., antihistamines, epinephrine, IV corticosteroids).1 Consider discontinuance of the drug.1

Cautious use recommended in patients who previously received the drug.1 Unknown risk of increased immunologic reaction with repeated administration.1 Immediately discontinue infusion and institute appropriate therapy if an anaphylactoid reaction occurs.1

Specific Populations

Pregnancy

Category C.1

Weigh risks against benefits of therapy in pregnant women.1 2 Some clinicians consider alteplase for ischemic stroke to be contraindicated in pregnant women.a

Lactation

Not known if distributed in milk; cautious use recommended.1

Pediatric Use

Safety and efficacy not established with IV alteplase.1 221 However, used with some success in a few infants and children with thrombosis of the vena cava, aorta, or peripheral arteries.286 287 288

Safety and efficacy of intracatheter instillation in neonates, children, and adolescents (2 weeks to 17 years of age) with occluded central venous catheters similar to that in adults.325

Thrombolytic therapy generally not recommended for treatment of venous thromboembolism in neonates and children unless vessel occlusion is life-threatening and/or causes organ dysfunction.1013 If thrombolysis is required, ACCP states that alteplase is the drug of choice; alteplase exhibits greater fibrin specificity, lower immunogenicity, and more effective clot lysis in vitro compared with streptokinase or urokinase (both no longer commercially available in the US).1013

ACCP states that thrombolytic therapy generally not recommended in children with arterial ischemic stroke.1013

Geriatric Use

Assess risks against the anticipated benefits of therapy in patients >75 years of age.1 2 Intracranial hemorrhage and other major bleeding complications more common.62 154 156

Hepatic Impairment

Limited data in animals suggests possible prolonged elimination half-life of t-PA in patients with severely impaired hepatic function and/or hepatic blood flow.46 185 221 Weigh anticipated benefits against risks of possible hemostatic defects associated with severe hepatic disease.1

Common Adverse Effects

Hemorrhage.1 2 31 32 33 34 36 37 38 39 40 41 43 44 45 46 47 48 154 155 198

Interactions for Alteplase

Anticoagulants

Potential pharmacodynamic interaction (increased risk of hemorrhage).1 14 34 43 44 68 72 74 144 155

Careful monitoring recommended, especially at arterial puncture sites.1 34 37 38 39 40 41 43 44 49 59 65 72 144 155 If serious bleeding occurs, immediately discontinue anticoagulant therapy and institute appropriate treatment as necessary.1 14

Drugs Affecting Platelet Function

Potential pharmacodynamic interaction (increased risk of bleeding complications, notably intracranial hemorrhage).193 194 357

Specific Drugs

Drug

Interaction

Comments

Abciximab

Increased risk of hemorrhage1

ACE inhibitors

Increased risk of orolingual angioedema1

Aspirin

Increased risk of hemorrhage1 357

In acute stroke, use not recommended within 24 hours of a thrombolytic agent because of increased risk of bleeding357

Dipyridamole

Increased risk of hemorrhage1

Heparin

Increased risk of hemorrhage1 14 34 43 44 68 72 74 144 155

Monitor carefully, especially at arterial puncture sites;1 34 37 38 39 40 41 43 44 49 59 65 72 144 155 if serious bleeding occurs, discontinue heparin and use protamine sulfate for reversal of effect1 14

Thrombolytic agents

Potential for synergistic thrombolytic effects4 13 189 190 191 192

Warfarin

Increased risk of hemorrhage1

Monitor carefully, especially at arterial puncture sites;1 34 37 38 39 40 41 43 44 49 59 65 72 144 155 if serious bleeding occurs, discontinue warfarin1 14

Alteplase Pharmacokinetics

Absorption

Onset

Thrombolysis of the infarct-related coronary artery usually occurs <1 hour after initiation of therapy.30 31 39 40 Lysis of pulmonary emboli usually occurs within 2–6 hours after initiation of therapy.86 87 88 91

Distribution

Extent

Not known whether alteplase crosses the placenta or distributes into milk or the CNS.3

Elimination

Metabolism

Cleared principally by the liver,1 3 5 8 9 10 12 27 46 130 131 which subsequently releases degradation products into the blood.10 11 27 130 131

Elimination Route

Excreted mainly in urine.130

Half-life

Patients with acute MI: mean 3.6–4.6 minutes for initial distribution phase (t½α) , mean 39–53 minutes for terminal elimination phase (t½β).65 Patients with thrombo-occlusive disease: mean 4.4 and 26.5 minutes for t½α and t½β, respectively.66

Special Populations

Prolonged elimination half-life in patients with severely impaired hepatic function and/or hepatic blood flow.46 185 221

Stability

Storage

Parenteral

Powder for Injection

≤30°C, or refrigerate at 2–8°C (Activase).1

Lyophilized powder for intracatheter instillation (Cathflo Activase): 2–8°C, protect from light.325

Reconstituted and diluted solutions contain no preservatives.1 2 Preferably use solutions immediately after preparation, but may be used for up to 8 hours after reconstitution or dilution.1 2 Discard any unused solution after 8 hours.1 2

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible

Sodium Chloride 0.9%

Incompatible

Dextrose 5% in water

Drug Compatibility
Admixture Compatibility.HID

Compatible

Lidocaine HCl

Morphine Sulfate

Nitroglycerin

Incompatible

Dobutamine HCl

Dopamine HCl

Heparin Sodium

Y-Site CompatibilityHID

Compatible

Lidocaine HCl

Metoprolol Tartrate

Propranolol HCl

Incompatible

Bivalirudin

Dobutamine HCl

Dopamine HCl

Heparin Sodium

Nitroglycerin

Actions

  • Thrombolytic agent;4 5 8 11 12 13 14 15 19 21 31 35 36 46 62 67 a biosynthetic (recombinant DNA origin) form of the enzyme human tissue-type plasminogen activator (t-PA).1 2 46

  • Hydrolyzes the arginine560-valine561 peptide bond in plasminogen to form the active proteolytic enzyme plasmin.4 5 7 8 12 106

  • A relatively fibrin-selective plasminogen activator.1 2 4 5 7 8 11 12 13 14 19 21 46 106 Fibrinolytic activity localized to the site of the thrombus due to formation of a ternary complex between t-PA, fibrin, and plasminogen.2 4 5 8 19 28 Induces thrombolysis without substantially activating circulating plasminogen15 29 or degrading fibrinogen.15 23 28 29 58

  • May transiently activate the coagulation system and decrease the patency of successfully reperfused infarct-related arteries.312 313 316

Advice to Patients

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.111 118 120

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs.214

  • Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Alteplase (Recombinant DNA Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

50 mg

Activase (with sterile water for injection diluent)

Genentech

100 mg

Activase (with sterile water for injection diluent)

Genentech

For solution, for IV catheter clearance

2 mg

Cathflo Activase

Genentech

AHFS DI Essentials. © Copyright 2018, Selected Revisions October 23, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Genentech, Inc. Activase (alteplase, recombinant) prescribing information. South San Francisco, CA; 2005 Dec.

2. Genentech, Inc. Activase (alteplase, recombinant) product monograph. South San Francisco, CA; 1987.

3. Genentech, Inc. Activase (alteplase, recombinant) product information form for American Hospital Formulary Service. South San Francisco, CA; 1987 Nov 13.

4. Collen D, Stump DC, Gold HK. Thrombolytic therapy. Ann Rev Med. 1988; 39:405-23. http://www.ncbi.nlm.nih.gov/pubmed/3130773?dopt=AbstractPlus

5. Tiefenbrunn AJ, Robison AK, Sobel BE. Clinical pharmacology of coronary thrombolysis. Cardiol Clin. 1987; 5:125-8. http://www.ncbi.nlm.nih.gov/pubmed/3103917?dopt=AbstractPlus

6. Conard J, Samama MM. Theoretic and practical considerations on laboratory monitoring of thrombolytic therapy. Semin Thromb Hemost. 1987; 13:212-22. http://www.ncbi.nlm.nih.gov/pubmed/3114887?dopt=AbstractPlus

7. Robison AK, Collen D. Activation of the fibrinolytic system. Cardiol Clin. 1987; 5:13-9. http://www.ncbi.nlm.nih.gov/pubmed/3103919?dopt=AbstractPlus

8. Collen D, Lijnen HR. Tissue-type plasminogen activator: mechanism of action and thrombolytic properties. Haemostasis. 1986; 16(Suppl 3):25-32. http://www.ncbi.nlm.nih.gov/pubmed/3095195?dopt=AbstractPlus

9. von Kaulla KN, Kaye H, von Kaulla E et al. Changes in blood coagulation before and after hepatectomy or transplantation in dogs and man. Arch Surg. 1966; 92:71-9. http://www.ncbi.nlm.nih.gov/pubmed/5322193?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3035840&blobtype=pdf

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