Alteplase (Monograph)

Brand names: Activase, Cathflo Activase
Drug class: Thrombolytic Agents

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Thrombolytic agent;¹ ⁴⁶ biosynthetic (recombinant DNA origin) form of human tissue-type plasminogen activator (t-PA).¹ 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 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 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 ⁸⁵ ¹¹⁷ ¹⁴¹ ¹⁵⁴ ¹⁵⁵ ¹⁶³ ¹⁹³ ¹⁹⁴ ²²⁶ ⁵²⁷

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, ⁴⁸ ¹⁹³ improve ventricular function,¹ ⁴ ³⁸ ⁴² ⁴⁶ ⁴⁷ ⁴⁸ ⁵⁰ ⁶⁹ ¹⁹³ and reduce the incidence of heart failure¹ 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 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

The risk of stroke may outweigh the benefit of thrombolytic therapy in patients whose acute MI places them at low risk for death or heart failure.¹

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 ¹¹⁰²

ACCP also recommends systemic thrombolytic therapy in selected patients with acute pulmonary embolism who clinically deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have an acceptable bleeding risk.¹¹⁰²

Acute Ischemic Stroke

Management of acute ischemic stroke to improve neurologic recovery and reduce the incidence of disability.¹ ⁴ ⁵ ⁶ ³²² ³⁵⁷ ³⁵⁸ ³⁷⁸ ³⁷⁹ ³⁸⁷ ³⁸⁸ ³⁸⁹ ³⁹⁰ ³⁹¹ ³⁹² ³⁹³ ³⁹⁴ ³⁹⁵ ³⁹⁶ ³⁹⁷ ¹⁰⁰⁹ ¹¹⁰¹

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 ¹¹⁰¹ 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 ≤1 hour.³⁸⁷ ³⁸⁸ ³⁸⁹ ³⁹⁰ ³⁹² ³⁹³ ³⁹⁶ ³⁹⁸ ¹¹⁰¹

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

Based on data from studies such as the WAKE-UP (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke) trial,⁴⁰⁵ the American Heart Association (AHA) and American Stroke Association (ASA) state that in patients with acute ischemic stroke who awake with stroke symptoms^{† [off-label]} or have unclear time of onset >4.5 hours^{† [off-label]} from last time known well or at baseline state, MRI to identify diffusion-positive fluid-attenuated inversion recovery (FLAIR)-negative lesions can be useful for selecting those who can benefit from IV alteplase administration within 4.5 hours of stroke symptom recognition.¹¹⁰¹

Use of thrombolytic therapy not recommended by ASA/AHA 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 ¹¹⁰¹

Arterial Thrombosis and Embolism

Intra-arterial thrombolytic therapy for lysis of arterial occlusions^{† [off-label]} 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 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

Has been used for clearing totally or partially occluded hemodialysis access catheters^{† [off-label]}.³⁵⁰ ³⁵¹ Studies involved similar dosing regimens as those currently used for clearing central venous catheters.²²¹

Alteplase Dosage and Administration

General

Pretreatment Screening

In patients with acute ischemic stroke who have not received recent anticoagulation therapy (e.g., oral anticoagulants, heparin), therapy with alteplase may be initiated prior to coagulation study results.¹ ¹¹⁰¹ However, infusion of alteplase should be discontinued if pretreatment coagulation study results are abnormal (as indicated by an INR >1.7 or an elevated aPTT).¹
In patients with acute ischemic stroke, obtain blood glucose concentrations prior to treatment with IV alteplase.¹¹⁰¹

Patient Monitoring

Frequently monitor and control blood pressure during and following IV infusion of alteplase in patients with acute ischemic stroke.¹ AHA/ASA state that systolic/diastolic blood pressure should be maintained at <180/105 mm Hg for the first 24 hours after IV alteplase treatment.¹¹⁰¹
Carefully monitor all potential bleeding sites (e.g., sites of all venous cutdowns, arterial and venous punctures, needle punctures).¹ ¹⁴ ¹⁵ ⁴⁴ ⁴⁶ ¹⁵⁴
Routine monitoring of hemostatic indices (e.g., fibrinogen concentrations or thrombin times) during therapy for acute MI is generally not recommended;¹⁵ ²²² however, monitoring hemostatic function has been suggested for patients who exhibit bleeding.²²² Determination of plasma fibrinogen also may be useful after discontinuance of thrombolytic therapy for correcting potential hemostatic abnormalities before anticipated surgery or other invasive procedures; monitoring of other coagulation indices (e.g., activated partial thromboplastin time) may be indicated for adjusting subsequent anticoagulant therapy.⁶ ¹⁵ ²²²
Monitor patients for hypersensitivity reactions and treat appropriately.¹ ³²⁵

Dispensing and Administration Precautions

Based on the Institute for Safe Medication Practices (ISMP), alteplase is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.⁴⁰⁸
The ISMP list of error-prone abbreviations, symbols, and dose designations states that the use of abbreviations for alteplase (e.g., t-PA) during the medication use process should be avoided as their use has been associated with serious medication errors.¹¹⁰⁴

Other General Considerations

Institute therapy as soon as possible after acute MI.¹ ³¹ ³² ³³ ³⁴ ³⁵ ³⁶ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴² ⁴³ ⁴⁶ ⁴⁷ ⁴⁸
In patients with acute ischemic stroke, administer in facilities that can provide appropriate evaluation and management of intracranial hemorrhage.¹
Initiate therapy for acute ischemic stroke within 3–4.5 hours of symptom onset.¹ ³²² ³⁵⁷ ³⁵⁸ ³⁹² ³⁹⁴ ³⁹⁵ ³⁹⁶ ¹⁰⁰⁹ ¹¹⁰¹ Prior to administration, exclude intracranial hemorrhage by cranial CT scan or other sensitive diagnostic imaging method.¹ ³²² ¹¹⁰¹

Administration

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

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

Also has been administered by intracoronary^{† [off-label]} 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 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 Accelerated infusion regimen only studied with concomitant administration of heparin and aspirin.¹ Controlled studies comparing the 2 regimens not available.¹

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.¹ Do not use vial if a vacuum is not present.¹ Do not use diluents other than sterile water for injection without preservatives.¹

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 with 0.9% sodium chloride injection or 5% dextrose injection, using either polyvinyl chloride bags or glass vials.¹ 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 Mix solution with gentle swirling and/or slow inversion of the infusion container; avoid excessive agitation.¹

Do not add any other drugs to infusion solutions containing alteplase.¹

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

Standardize 4 Safety

Standardized concentrations for alteplase have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care.⁴⁰¹ ⁴⁰² Because recommendations from the S4S panels may differ from the manufacturer’s prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label.⁴⁰¹ ⁴⁰² For additional information on S4S (including updates that may be available), see [Web].⁴⁰¹ ⁴⁰²

Table 1: Standardize 4 Safety Continuous IV Infusion Standard Concentrations for Alteplase401402
Patient Population	Concentration Standards	Dosing Units
Pediatric patients (<50 kg)	1 mg/mL	mg/kg per hour
Adults	1 mg/mL	mg/hour

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

Pediatric Patients

Occluded 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

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

Adults

Acute MI

3-Hour Infusion

In adult weighing ≥65 kg, infuse total of 100 mg (58 million IU) over 3 hours.¹ Initially, infuse 60 mg (34.8 million IU) during the first hour; 6–10 mg of this dose is rapidly infused over 1–2 minutes.¹ Subsequently, infuse 20 mg (11.6 million IU) per hour for the next 2 hours.¹

In adults weighing <65 kg (lean or actual body weight, whichever is less), infuse 1.25 mg/kg over 3 hours.¹ ²²¹ Initially, infuse 0.75 mg/kg during the first hour; 0.075 mg/kg of this dose is rapidly infused over 1–2 minutes.¹ ¹⁹⁹ ²²¹ Subsequently, infuse 0.25 mg/kg per hour for the next 2 hours.¹ ¹⁹⁹ ²²¹ Maximum recommended total dose is 100 mg.¹

Accelerated Infusion

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 Maximum 100 mg.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 parenteral anticoagulation therapy near the end of or immediately following alteplase infusion when aPTT or thrombin time returns to twice the normal value or less.¹

In the setting of cardiac arrest associated with pulmonary embolism, AHA guidelines suggest an alteplase dosage of 50 mg IV bolus with an option for a repeat bolus in 15 minutes.³⁶⁰

Acute Ischemic Stroke

IV

0.9 mg/kg (up to 90 mg) total dose.¹ ³⁵⁷ Initially, administer 10% of the dose rapidly over 1 minute.¹ Infuse remainder of dose over 60 minutes.¹ Do not exceed dose of 0.9 mg/kg (maximum 90 mg).¹

Occluded 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

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

Special Populations

Geriatric Patients

Based on results of a trial with tenecteplase showing that an excess of intracranial hemorrhage in patients ≥75 years of age with acute MI was reduced after reducing the tenecteplase dosage by 50%,⁴¹³ some clinicians suggest considering a 50% reduction in the dosage of alteplase in patients ≥75 years of age receiving the drug for acute MI.⁴¹⁴

Cautions for Alteplase

Contraindications

Active internal bleeding.¹
History of recent stroke.¹
Intracranial neoplasm.¹
Aneurysm.¹
Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma.¹
Bleeding diathesis.¹ ¹⁵⁴
Arteriovenous malformation.¹ ¹⁵⁴
Current severe uncontrolled hypertension.¹ ¹⁵⁴

Current intracranial hemorrhage, subarachnoid hemorrhage, history of intracranial hemorrhage, or active internal bleeding.¹ ³²² ³⁵⁸ ¹¹⁰¹
Extensive regions of clear hypoattenuation on CT brain imaging.¹¹⁰¹
Bleeding diathesis.¹ ³²² ³⁵⁸
Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or prior ischemic stroke.¹ ³²² ³⁵⁸ ¹¹⁰¹
Current severe uncontrolled hypertension.¹ ³²² ³⁵⁸ ¹¹⁰¹
Arteriovenous malformation or aneurysm.¹ ³²² ³⁵⁸
Symptoms consistent with infective endocarditis.¹¹⁰¹
Stroke known or suspected to be associated with aortic arch dissection.¹¹⁰¹
Intracranial neoplasm.¹ ³²² ³⁵⁸ ¹¹⁰¹
Structural GI malignancy.¹¹⁰¹
Thrombocytopenia (platelets <100,000/mm³), INR >1,7, aPTT >40 seconds, or PT >15 seconds.¹¹⁰¹
Treatment dose of low molecular weight heparin with previous 24 hours.¹¹⁰¹
Current treatment with direct thrombin inhibitors or direct factor Xa inhibitors unless laboratory tests are normal or >48 hours since a dose of these agents was received (assuming normal renal metabolizing function).¹¹⁰¹

Warnings/Precautions

Effects on Hemostasis

Alteplase can cause serious, sometimes fatal, internal and external bleeding, especially at arterial and venous puncture sites.¹

Possible bleeding and hemorrhagic complications,¹ ¹⁴ ⁴³ ⁴⁴ ⁶² ¹⁴⁵ ¹⁴⁶ ¹⁵⁴ ¹⁵⁵ ¹⁵⁶ including intracranial hemorrhage and other major bleeding complications.¹⁴¹ May be more common in geriatric patients¹ ⁶² ¹⁵⁴ ¹⁵⁶ and those with a history of cerebrovascular accident or severe or poorly controlled hypertension.¹⁴¹

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),¹ ³²² high likelihood of hemostatic defects (e.g., secondary to severe hepatic or renal disease), internal (e.g., GI or GU) bleeding, acute pericarditis, subacute bacterial endocarditis, pregnancy, septic thrombophlebitis or occluded arteriovenous cannula at seriously infected site, recent intracranial hemorrhage, or recent (within 2–4 weeks) trauma.¹ Also, weigh risks against benefits of therapy in patients with diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions.¹ Weigh risks against benefits in patients receiving concurrent oral anticoagulant therapy (e.g., warfarin).¹ 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

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 Avoid IM injections and nonessential handling of patient.¹ ⁴⁶ Perform invasive venous procedures carefully and as infrequently as possible.¹ ⁴⁶ Avoid arterial and venous invasive procedures in areas inaccessible to manual compression (e.g., internal jugular or subclavian punctures) before and during therapy.¹ Use of an artery in an upper extremity (e.g., radial or brachial) is preferable if arterial puncture is essential.¹ ⁴⁶ 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, retroperitoneal, GU, GI bleeding).¹ ³³ ³⁶ ³⁹ ⁴¹ ⁴³ ⁴⁴ ⁴⁷ ⁴⁸ ¹⁵⁴ Upper airway hemorrhage (sometimes fatal) at site of traumatic intubation reported.¹ 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

Aspirin and heparin have been administered concomitantly with and following infusions of alteplase in patients with acute MI and pulmonary embolism; however, concomitant administration of heparin and aspirin with and following infusions of alteplase for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been studied.¹ Because heparin, aspirin, or alteplase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites.¹ Hemorrhage can occur one or more days after administration of alteplase, while patients are still receiving anticoagulant therapy.¹

If serious bleeding occurs, immediately discontinue alteplase therapy¹ ¹⁴ and initiate appropriate treatment.¹ ¹⁴ ¹⁵ 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

Coagulation tests and measures of fibrinolytic activity may be unreliable during alteplase therapy, unless specific precautions are taken to prevent in vitro artifacts.¹ When present in blood at pharmacologic concentrations, alteplase remains active under in vitro conditions, which can result in degradation of fibrinogen in blood samples removed for analysis.¹

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

Possible increased risk of thromboembolic events in patients with high likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation.¹ Alteplase not shown to adequately treat underlying deep vein thrombosis in patients with pulmonary embolism; consider possible risk of re-embolization due to lysis of underlying deep vein thrombi in such patients.¹

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

Potential new embolic episodes, including those involving cerebral vessels.¹⁹⁶ 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

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 the incidence of reocclusion through concomitant anticoagulation (e.g., heparin and/or oral anticoagulants)¹ 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 prolonged infusion of the thrombolytic agent, or mechanical or surgical revascularization procedures.⁴ ¹⁴ ³⁵ ³⁷ ³⁸ ⁶² ⁶³ ¹⁷⁷

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.¹ ³²²

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 ; clinicians also suggest weighing risks against anticipated benefits in patients with major early infarct signs on CT scan (e.g., substantial edema, mass effect, midline shift).³⁵⁸ However, AHA and ASA state that thrombolytic therapy almost always should not be administered to patients with major early infarct signs.³⁵⁸ ¹¹⁰¹

In patients with acute ischemic stroke, administer in facilities that can provide appropriate evaluation and management of intracranial hemorrhage.¹ Frequently monitor and control BP during and following administration.¹ ³⁵⁷ Safety of administration without careful BP management not established.¹ ³²²

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, hypertension, pancreatitis, MI, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.¹ ²⁶⁷

Arrhythmias

Possible reperfusion-related atrial³² ¹⁶² ¹⁶³ ¹⁶⁴ ¹⁶⁶ and/or ventricular⁶⁷ ¹⁶² ¹⁶³ ¹⁶⁴ ¹⁶⁵ ¹⁸⁷ arrhythmias (e.g., accelerated idioventricular rhythm,⁶⁷ ¹⁵⁵ ¹⁶² ¹⁶³ ¹⁸⁷ ventricular premature complexes,⁶⁷ ¹⁶² ventricular fibrillation,¹⁶³ ¹⁶⁵ atrial premature complexes,¹⁶⁶ atrial fibrillation,³² ¹⁶⁶ junctional rhythm,¹⁶³ ventricular tachycardia,¹⁶² sinus bradycardia³² ⁶⁷ ¹⁵⁵ ¹⁶² ¹⁶³ ¹⁶⁴ ). Reperfusion-related arrhythmias usually are transient.¹⁸⁷

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

Hepatic Effects

Weigh anticipated benefits of alteplase therapy against increased risks in patients with substantial liver dysfunction.¹

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylactoid reaction, laryngeal edema, angioedema, rash, urticaria), in rare cases fatal, reported.¹ ¹⁴⁵ Many of the patients were receiving concomitant ACE inhibitors.¹

Monitor patients during and several hours following alteplase infusion for signs of hypersensitivity reactions (e.g., anaphylactoid reaction, angioedema).¹ Discontinue alteplase and promptly administer appropriate therapy (e.g., antihistamines, epinephrine, IV corticosteroids).¹

Hypersensitivity reactions (e.g., urticaria, angioedema, and anaphylaxis) reported in patients receiving alteplase by intracatheter instillation.³²⁵ Monitor patients for hypersensitivity reactions and treat appropriately if necessary.³²⁵

Specific Populations

Pregnancy

Experience in pregnant women insufficient to inform a drug-associated risk of adverse developmental outcomes.¹

Embryocidal in rabbits when administered IV during organogenesis at doses resulting in the clinical exposure for acute MI, but no maternal or fetal toxicity evident at lower exposure in pregnant rats or rabbits.¹

Possible increased risk of bleeding when thrombolytic therapy administered during pregnancy.¹ Weigh risks against benefits of therapy in pregnant women.¹ ¹¹⁰¹

Safety and efficacy for treatment of acute ischemic stroke not established in early postpartum period (<14 days after delivery).¹¹⁰¹

Lactation

Not known whether alteplase is distributed into human milk or whether drug affects breast-fed infant or milk production.¹

Females and Males of Reproductive Potential

Not known whether alteplase can affect fertility.¹

Pediatric Use

Safety and efficacy not established with IV alteplase.¹ 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 Intracranial hemorrhage and other major bleeding complications more common.¹ ⁶² ¹⁵⁴ ¹⁵⁶

Some clinicians suggest considering a 50% reduction in the dosage of alteplase in patients ≥75 years of age receiving the drug for acute MI.⁴¹⁴

Hepatic Impairment

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

Common Adverse Effects

Common adverse effects (reported in >5% of patients): Hemorrhage.¹ ³¹ ³² ³³ ³⁴ ³⁶ ³⁷ ³⁸ ³⁹ ⁴⁰ ⁴¹ ⁴³ ⁴⁴ ⁴⁵ ⁴⁶ ⁴⁷ ⁴⁸ ¹⁵⁴ ¹⁵⁵ ¹⁹⁸

Drug Interactions

Thrombolytic Agents

Further studies needed to determine the efficacy and safety of alteplase therapy combined with other thrombolytic agents in patients with acute MI.²²¹

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).¹ ¹⁹³ ¹⁹⁴ ³⁵⁷

Specific Drugs

Drug	Interaction	Comments
Abciximab	Increased risk of hemorrhage¹	AHA and ASA state to avoid concurrent administration with IV alteplase in patients with acute ischemic stroke¹¹⁰¹
ACE inhibitors	Increased risk of angioedema¹
Aspirin	Increased risk of hemorrhage¹ ³⁵⁷	In acute stroke, use generally not recommended within 24 hours of a thrombolytic agent because of increased risk of bleeding³⁵⁷ ¹¹⁰¹ AHA/ASA state to avoid administration of IV aspirin within 90 minutes of starting IV alteplase treatment¹¹⁰¹ AHA/ASA state that in patients with acute ischemic stroke, obtain follow-up CT or MRI scan at 24 hours after IV alteplase before starting treatment with antiplatelet agents¹¹⁰¹
Dipyridamole	Increased risk of hemorrhage¹	AHA/ASA state that in patients with acute ischemic stroke, obtain follow-up CT or MRI scan at 24 hours after IV alteplase before starting treatment with antiplatelet agents¹¹⁰¹
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 AHA/ASA state that in patients with acute ischemic stroke, obtain follow-up CT or MRI scan at 24 hours after IV alteplase before starting treatment with anticoagulant agents¹¹⁰¹
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 AHA/ASA state that in patients with acute ischemic stroke, obtain follow-up CT or MRI scan at 24 hours after IV alteplase before starting treatment with anticoagulant agents¹¹⁰¹

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

Elimination

Metabolism

Cleared principally by the liver,¹ 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 (t_½α) , mean 39–53 minutes for terminal elimination phase (t_½β).⁶⁵ Patients with thrombo-occlusive disease: mean 4.4 and 26.5 minutes for t_½α and t_½β, respectively.⁶⁶

Special Populations

Prolonged elimination half-life in patients with severely impaired hepatic function and/or hepatic blood flow.⁴⁶ ¹⁸⁵ ²²¹ ³²⁵

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.¹ ³²⁵ Preferably use solutions immediately after preparation, but may be used for up to 8 hours after reconstitution or dilution when stored at 2-30ºC.¹ ³²⁵ Discard any unused solution after 8 hours.¹ ³²⁵

Actions

Thrombolytic agent;¹ 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 ⁴⁶
Hydrolyzes the arginine⁵⁶⁰-valine⁵⁶¹ peptide bond in plasminogen to form the active proteolytic enzyme plasmin.⁴ ⁵ ⁷ ⁸ ¹²
A relatively fibrin-selective plasminogen activator.¹ ⁴ ⁵ ⁷ ⁸ ¹¹ ¹² ¹³ ¹⁴ ¹⁹ ²¹ ⁴⁶ Fibrinolytic activity localized to the site of the thrombus due to formation of a ternary complex between t-PA, fibrin, and plasminogen.¹ 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

Risk of bleeding.¹ Advise patients to contact clinicians if they experience symptoms or signs consistent with bleeding (e.g., unusual bruising, pink or brown urine, red or black or tarry stools, coughing up blood, vomiting blood or blood that looks like coffee grounds), headache, or stroke symptoms.¹
Advise patients to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses or recent surgery.¹ ³²⁵
Advise females of reproductive potential to inform clinicians if they are or plan to become pregnant or plan to breast-feed.¹ ³²⁵
Inform patients of other important precautionary information.¹ ³²⁵

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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

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

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91. Goldhaber SZ, Kessler CM, Heit J et al. Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet. 1988; 2:293-8. https://pubmed.ncbi.nlm.nih.gov/2899718

92. Come PC, Kim D, Parker JA et al. Early reversal of right ventricular dysfunction in patients with acute pulmonary embolism after treatment with IV tissue plasminogen activator. J Am Coll Cardiol. 1987; 10:971-8. https://pubmed.ncbi.nlm.nih.gov/2959713

93. Goldhaber SZ, Meyerovitz MF, Markis JE et al. Thrombolytic therapy of acute pulmonary embolism: current status and future potential. J Am Coll Cardiol. 1987; 10(Suppl):96B-104. https://pubmed.ncbi.nlm.nih.gov/3117862

94. Graor RA, Risius B, Young JR et al. Peripheral artery and bypass graft thrombolysis with recombinant human tissue-type plasminogen activator. J Vasc Surg. 1986; 3:115-24. https://pubmed.ncbi.nlm.nih.gov/3079838

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