Alteplase

Class: Thrombolytic Agents
Brands: Activase, Cathflo Activase

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

Coronary Artery Thrombosis and MI

Management of selected cases of acute evolving transmural MI,^{1 2 34 37 38 41 42 43 46 47 48 65 75 80 83 141 193 352 353} with heparin and/or platelet-aggregation inhibitors (e.g., aspirin, clopidogrel, GP IIb/IIIa-receptor inhibitors) as adjunctive therapy.^{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 85 117 141 154 155 163 168 193 327 352 353 360} Lysis of coronary artery thrombi associated with acute evolving transmural MI^{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} and the resulting reperfusion can limit infarct size,^{1 48 193} improve ventricular function,^{1 2 4 38 42 46 47 48 50 69 193 353} and reduce the incidence of CHF^{1 2 38} and associated post-MI mortality.^{1 42 46 193 194 226}

Greater benefit in patients with an anterior MI, left bundle branch block, a history of diabetes mellitus, prior MI, hypotension (SBP <100 mm Hg), or tachycardia (>100 bpm).^{47 48 242 311 352}

Clinical benefit diminishes as the time period from symptom onset to initiation of therapy increases.^{42 51 52 67 68 193 205 309 311 319} If possible, administer thrombolytic therapy within 30 minutes of hospital admission or first contact with the health-care system.^{327 352 353 360}

Use of alteplase or tenecteplase rather than streptokinase (no longer commercially available in US) recommended by the American College of Chest Physicians (ACCP) in patients with acute MI who can be treated within 6 hours of symptom onset.^{326 353}

Delayed therapy (e.g., initiated within 7–24 hours) may benefit patients with persisting ischemic pain and ST-segment elevation or left bundle branch block.^{310 311 353}

Not routinely recommended for patients presenting 12–24 hours after onset of MI symptoms.^{310 319}

ACCP, ACC, and AHA currently recommend consideration of either thrombolytic therapy or urgent angiography and PCI for the reduction of mortality in patients with an acute evolving MI.^{310 311 327 352 360}

ACCP suggests thrombolytic therapy in high-risk patients with ischemic symptoms characteristic of an acute MI or hemodynamic compromise present for 12–24 hours who have persistent ST-segment elevation or left bundle-branch block with concomitant ST-segment elevation changes if primary PCI is not readily available.³⁵³ ACC and AHA state that thrombolytic therapy is reasonable within 12–24 hours of symptom onset in patients with persistent ischemic symptoms accompanied by ST-segment elevation, provided no contraindications exist.^{352 360}

Thrombolytic therapy may be reasonable in patients with true posterior MI presenting within 12 hours after onset of symptoms, provided no contraindications exist.^{352 353 360}

ACCP recommends against use of thrombolytic therapy with or without a GPIIb/IIIa inhibitor in patients undergoing primary PCI for acute ST-segment elevation MI.³⁵³

PE

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 93 269 270 271 272 273 274 275 276 355}

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 93 269 270 271 272 273 274 275 276 314 355}

Generally reserve IV thrombolytic therapy for those with acute massive PE accompanied by unstable hemodynamics (e.g., shock) who do not have major contraindications because of bleeding risk or those with stable hemodynamics with other poor prognostic factors (e.g., marked dyspnea, anxiety, and low oxygen saturation; elevated troponin concentrations indicating right ventricular microinfarction; echocardiographic evidence of right ventricular dysfunction, right ventricular enlargement on a chest computed-tomography [CT] scan).³⁵⁵

Perform a rapid risk assessment to determine if thrombolytic therapy is appropriate; irreversible cardiogenic shock may occur if therapy is delayed in patients with evidence of hemodynamic compromise.³⁵⁵

Acute Ischemic Stroke

Management of acute ischemic stroke to improve neurologic recovery and reduce the incidence of disability.^{1 2 3 4 5 6 315 322 354 357 358 360 378 379 387 388 389 390 391 392 393 394 395 396 397}

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.^{1 315 322 354 357 358 360 392 394 395 396} 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 2 315 322 354 357 394 395} 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).^{354 358 360}

Use of thrombolytic therapy not recommended in patients with minor neurologic deficit or with rapidly improving symptoms.^{1 315 354 360}

Occluded IV Catheters

Restoration of patency to central venous catheters obstructed by a thrombus (assessed by the ability to withdraw blood).^{325 359}

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

Arterial Thrombosis and Embolism

Intra-arterial thrombolytic therapy for lysis of arterial occlusions† in peripheral vessels and bypass grafts^{94 95 96 97 98 318 356} in patients with acute (<14 days old) thromboembolic arterial ischemia.^{318 356} Such patients should have a low risk for the development of myonecrosis and ischemic nerve damage in the affected extremity during therapy.^{318 356}

Alteplase Dosage and Administration

General

• 
  

  Institute therapy as soon as possible after an acute MI^{1 2 14 31 32 33 34 35 36 37 38 39 40 41 42 43 46 47 48 352} (preferably within 3–6 hours).^{4 14 222 309 352 310 311} (See Coronary Artery Thrombosis and MI under Uses.)

  
  


• 
  

  Initiate therapy for acute ischemic stroke within 3–4.5 hours of symptom onset.^{1 315 322 354 357 358 392 394 395 396} Prior to administration, exclude intracranial hemorrhage by cranial CT scan or other sensitive diagnostic imaging method.^{1 315 322 354} 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 90 102 103 104 354} 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} An accelerated infusion regimen generally is recommended by ACCP, ACC, and AHA.^{310 311 353}

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.³⁵⁹ 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, further evaluation required to determine cause of the occlusion.³⁵⁹

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.³⁵⁹ 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, further evaluation required to determine cause of the occlusion.³⁵⁹

Adults

Coronary Artery Thrombosis and 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 7 352} Initially, inject 15 mg rapidly over 1–2 minutes,^{1 7 352} followed by 50 mg over the next 30 minutes, then 35 mg over the next hour.^{1 352}

Alternatively, in patients weighing ≤67 kg, inject 15 mg rapidly over 1–2 minutes,^{1 7 352} 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.^{1 352}

PE

IV

100 mg (58 million IU) infused over 2 hours.^{1 91 271 273 355} Prior to administration of thrombolytic therapy, administer IV unfractionated heparin in full treatment dosages; may continue or temporarily interrupt heparin therapy during alteplase infusion.³⁵⁵ 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.^{1 355}

Acute Ischemic Stroke

IV

0.9 mg/kg (up to 90 mg) infused over 1 hour.^{1 354 357} 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.³⁵⁹

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, further evaluation required to determine cause of the occlusion.³⁵⁹

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 2 310 311 352 353}

  
  


• 
  

  History of cerebrovascular accident or intracranial hemorrhage.^{1 2 310 311 352 353}

  
  


• 
  

  Intracranial neoplasm.^{1 2 310 311 352 353}

  
  


• 
  

  Aneurysm.^{1 2 310 311 352 353}

  
  


• 
  

  Recent intracranial or intraspinal surgery or trauma.^{1 2 310 311 352 353}

  
  


• 
  

  Known bleeding diathesis.^{1 2 154 310 311 352}

  
  


• 
  

  Arteriovenous malformation.^{1 2 154 310 311 352}

  
  


• 
  

  Severe uncontrolled hypertension.^{1 2 154 310 311 352}

  
  


• 
  

  Suspected aortic dissection.^{1 2 154 310 311 352}

  
  

• 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.^{1 315 322 354 358 360}

  
  


• 
  

  Known bleeding diathesis.^{1 315 322 354 358 360}

  
  


• 
  

  Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or recent previous stroke.^{1 315 322 354 358 360}

  
  


• 
  

  Uncontrolled hypertension at time of treatment (e.g., SBP or DBP>185 or 110 mm Hg, respectively) or hypertension requiring aggressive treatment.^{1 315 322 354 358 360}

  
  


• 
  

  Arteriovenous malformation or aneurysm.^{1 315 322 354 358 360}

  
  


• 
  

  Seizure at onset of stroke.^{1 315 322 354 358 360}

  
  


• 
  

  Intracranial neoplasm.^{1 315 322 354 358 360}

  
  

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.^{141 222 319} May be more common in geriatric patients,^{62 154 156 319} patients with low body weight,³¹⁹ and those with a history of cerebrovascular accident or severe or poorly controlled hypertension.^{141 222 319}

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 2 310 311 315 319 322} 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 2 222 310 311 315} Also, weigh risks against benefits of therapy in patients with diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions.^{1 2 310 311} Weigh risks against benefits in patients receiving concurrent oral anticoagulant therapy (e.g., warfarin).^{1 2 310 311} 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 2 310 311}

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.^{1 221 222 354} 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 therapy^{1 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 2 222 310 311 315}

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}