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Alteplase

Pronunciation

Pronunciation

(AL te plase)

Index Terms

  • Alteplase Recombinant
  • Alteplase, Tissue Plasminogen Activator, Recombinant
  • tPA

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection:

Cathflo Activase: 2 mg (1 ea)

Solution Reconstituted, Intravenous:

Activase: 50 mg (1 ea); 100 mg (1 ea)

Brand Names: U.S.

  • Activase
  • Cathflo Activase

Pharmacologic Category

  • Thrombolytic Agent

Pharmacology

Initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converts entrapped plasminogen to plasmin

Distribution

Vd (initial): Approximates plasma volume

Excretion

Clearance (in patients with acute MI receiving accelerated regimen): Rapidly from circulating plasma (572 ± 132 mL/minute) (Tanswell 1992), primarily hepatic; >50% present in plasma is cleared within 5 minutes after the infusion is terminated, ~80% cleared within 10 minutes (Semba 2000)

Duration of Action

>50% present in plasma cleared ~5 minutes after infusion terminated, ~80% cleared within 10 minutes; fibrinolytic activity persists for up to 1 hour after infusion terminated (Semba 2000)

Half-Life Elimination

Initial: 5 minutes

Use: Labeled Indications

Activase:

Acute ischemic stroke: Treatment of acute ischemic stroke (AIS)

Pulmonary embolism: Management of acute massive pulmonary embolism (PE)

ST-elevation myocardial infarction: Management of ST-elevation myocardial infarction (STEMI) for the lysis of thrombi in coronary arteries.

Limitations of use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose acute myocardial infarction (MI) puts them at low risk for death or heart failure.

Recommended criteria for treatment:

STEMI (ACCF/AHA [O’Gara 2013]): Ischemic symptoms within 12 hours of treatment or evidence of ongoing ischemia 12 to 24 hours after symptom onset with a large area of myocardium at risk or hemodynamic instability.

STEMI ECG definition: New ST-segment elevation at the J point in at least 2 contiguous leads of ≥2 mm (0.2 mV) in men or ≥1.5 mm (0.15 mV) in women in leads V2-V3 and/or of ≥1 mm (0.1 mV) in other contiguous precordial leads or limb leads. New or presumably new left bundle branch block (LBBB) may interfere with ST-elevation analysis and should not be considered diagnostic in isolation.

At non-PCI-capable hospitals, the ACCF/AHA recommends thrombolytic therapy administration when the anticipated first medical contact (FMC)-to-device time at a PCI-capable hospital is >120 minutes due to unavoidable delays.

AIS: Onset of stroke symptoms within 3 hours of treatment

Acute PE: Age ≤75 years: Documented massive PE (defined as acute PE with sustained hypotension [SBP <90 mm Hg for ≤15 minutes or requiring inotropic support], persistent profound bradycardia [HR <40 bpm with signs or symptoms of shock], or pulselessness); alteplase may be considered for submassive PE with clinical evidence of adverse prognosis (eg, new hemodynamic instability, worsening respiratory insufficiency, severe right ventricular (RV) dysfunction, or major myocardial necrosis) and low risk of bleeding complications. Note: Not recommended for patients with low-risk PE (eg, normotensive, no RV dysfunction, normal biomarkers) or submassive acute PE with minor RV dysfunction, minor myocardial necrosis, and no clinical worsening (AHA [Jaff 2011]).

Cathflo Activase: Restoration of function to central venous access device

Use: Unlabeled

Acute ischemic stroke presenting 3-4.5 hours after symptom onset; acute peripheral arterial occlusion; infected parapneumonic effusion (with [adult] or without [pediatric] dornase alfa); prosthetic valve thrombosis; intra-arterial administration for patients with acute ischemic stroke who have contraindications to IV use (Note: Intra-arterial administration requires patient to be at an experienced stroke center with rapid access to cerebral angiography and qualified interventionalists)

Contraindications

Hypersensitivity to alteplase or any component of the formulation

Treatment of STEMI or PE: Active internal bleeding; history of recent stroke; recent (within 3 months [ACCF/AHA: Within 2 months]) intracranial or intraspinal surgery or serious head trauma; presence of intracranial conditions that may increase the risk of bleeding (eg, intracranial neoplasm, arteriovenous malformation, aneurysm); known bleeding diathesis; severe uncontrolled hypertension (ACCF/AHA: Unresponsive to emergency therapy)

Additional contraindications according to the American Heart Association and American College of Cardiology Foundation (AHA [Jaff 2011]; ACCF/AHA [O’Gara 2013]): Active bleeding (excluding menses); any prior intracranial hemorrhage; suspected aortic dissection; ischemic stroke within 3 months except when within 4.5 hours; significant closed head or facial trauma within 3 months with radiographic evidence of bony fracture or brain injury

Treatment of AIS: Current intracranial hemorrhage; subarachnoid hemorrhage; active internal bleeding; recent (within 3 months) intracranial or intraspinal surgery or serious head trauma; presence of intracranial conditions that may increase the risk of bleeding (eg, intracranial neoplasm, arteriovenous malformation, aneurysm); known bleeding diathesis; severe uncontrolled hypertension

Additional contraindications according to the American Heart Association/American Stroke Association 2013 guidelines (AHA/ASA [Jauch 2013]): History of intracranial hemorrhage; suspicion of subarachnoid hemorrhage; stroke within 3 months; arterial puncture at a noncompressible site in previous 7 days; uncontrolled hypertension at time of treatment (eg, >185 mm Hg systolic or >110 mm Hg diastolic); multilobar cerebral infarction (hypodensity >1/3 cerebral hemisphere); known bleeding diathesis including but not limited to current use of oral anticoagulants with an INR >1.7 (or PT >15 seconds), current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests (eg, aPTT, INR, ECT, TT, or appropriate factor Xa activity assays) (See “Note”), administration of heparin within 48 hours preceding the onset of stroke with an elevated aPTT greater than the upper limit of normal, or platelet count <100,000/mm3.

Note: The AHA/ASA 2013 guidelines do allow the use of alteplase in patients taking direct thrombin inhibitors (eg, dabigatran) or direct factor Xa inhibitors (eg, rivaroxaban) when sensitive laboratory tests (eg, aPTT, INR, ECT, TT, or appropriate direct factor Xa activity assays) are normal or the patient has not received a dose of these agents for >2 days (assuming normal renal function) (AHA/ASA [Jauch 2013]). The AHA/ASA 2016 scientific statement states that alteplase is not recommended in patients who have received LMWH (prophylactic or treatment doses) within the previous 24 hours (AHA/ASA [Demaerschalk 2016]).

Additional exclusion criteria within clinical trials:

Presentation <3 hours after initial symptoms (NINDS, 1995): Time of symptom onset unknown, rapidly improving or minor symptoms, major surgery within 2 weeks, GI or urinary tract hemorrhage within 3 weeks, aggressive treatment required to lower blood pressure, glucose level <50 or >400 mg/dL, and lumbar puncture within 1 week.

Note: The AHA/ASA 2016 scientific statement recommends alteplase use in patients presenting <3 hours after initial symptoms with mild but disabling stroke symptoms in the opinion of the treating physician. Alteplase is also reasonable in patients presenting <3 hours after initial symptoms with moderate-to-severe ischemic stroke who demonstrate early improvement, but remain moderately impaired and potentially disabled in the examiner's judgment (AHA/ASA [Demaerschalk 2016]).

Presentation 3 to 4.5 hours after initial symptoms (AHA/ASA [Jauch 2013]; ECASS-III; Hacke 2008): Age >80 years, time of symptom onset unknown, rapidly improving or minor symptoms, current use of oral anticoagulants regardless of INR, glucose level <50 or >400 mg/dL, aggressive intravenous treatment required to lower blood pressure, major surgery or severe trauma within 3 months, baseline National Institutes of Health Stroke Scale (NIHSS) score >25 [ie, severe stroke], and history of both stroke and diabetes.

Note: The AHA/ASA 2016 scientific statement has provided updated evidence on certain patients presenting in the 3 to 4.5 hour after initial symptoms window excluded in the aforementioned earlier guidelines, including: patients >80 years (alteplase use in the 3 to 4.5 window can be safe and as effective as younger patients); patients taking warfarin within an INR <1.7 (alteplase use appears safe and may be beneficial); patients with a history of both stroke and diabetes (alteplase use may be as effective as treatment in the 0 to 3 hour window, and may be a reasonable option) (AHA/ASA [Demaerschalk 2016]).

Dosing: Adult

Acute ischemic stroke: Activase: IV: Within 3 hours of the onset of symptom onset (labeled use) or within 3 to 4.5 hours of symptom onset (off-label use; Hacke 2008; Jauch 2013): Note: Perform noncontrast-enhanced CT or MRI prior to administration. Initiation of anticoagulants (eg, heparin) or antiplatelet agents (eg, aspirin) within 24 hours after starting alteplase is not recommended; however, initiation of aspirin within 24 to 48 hours after stroke onset is recommended (Jauch 2013). Initiation of SubQ heparin (≤10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3 to 4.5 hour window trial did not increase incidence of intracerebral hemorrhage (Hacke 2008).

Recommended total dose: 0.9 mg/kg (maximum total dose: 90 mg)

Patients ≤100 kg: Load with 0.09 mg/kg (10% of 0.9 mg/kg dose) as an IV bolus over 1 minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion over 60 minutes.

Patients >100 kg: Load with 9 mg (10% of 90 mg) as an IV bolus over 1 minute, followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes.

Central venous catheter clearance: Cathflo Activase (1 mg/mL): Intracatheter:

Patients <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg/2 mL; retain in catheter for 0.5 to 2 hours; may instill a second dose if catheter remains occluded

Patients ≥30 kg: 2 mg/2 mL; retain in catheter for 0.5 to 2 hours; may instill a second dose if catheter remains occluded

Pulmonary embolism (PE) (acute massive): Activase: IV: 100 mg over 2 hours; may be administered as a 10 mg bolus followed by 90 mg over 2 hours as was done in patients with submassive PE (Konstantinides 2002). Institute or resume parenteral anticoagulation near the end of or immediately following the alteplase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less. Note: Use in submassive PE is off-label.

ST-elevation myocardial infarction (STEMI): Activase: IV: Note: Manufacturer’s labeling recommends 3-hour infusion regimen; however, accelerated regimen preferred by the ACCF/AHA (O’Gara 2013).

Accelerated regimen (weight-based):

Patients >67 kg: Total dose: 100 mg over 1.5 hours; administered as a 15 mg IV bolus over 1 to 2 minutes followed by infusions of 50 mg over 30 minutes, then 35 mg over 1 hour. Maximum total dose: 100 mg

Patients ≤67 kg: Infuse 15 mg IV bolus over 1 to 2 minutes followed by infusions of 0.75 mg/kg (not to exceed 50 mg) over 30 minutes then 0.5 mg/kg (not to exceed 35 mg) over 1 hour. Maximum total dose: 100 mg

Note: Thrombolytic should be administered within 30 minutes of hospital arrival. Generally, there is only a small trend for benefit of therapy after a delay of 12 to 24 hours from symptom onset, but thrombolysis may be considered for selected patients with ongoing ischemic pain and extensive ST elevation; however, primary PCI is preferred in these patients. Administer concurrent aspirin, clopidogrel, and anticoagulant therapy (ie, unfractionated heparin, enoxaparin, or fondaparinux) with alteplase (O’Gara 2013).

Acute peripheral arterial occlusion (off-label use): Intra-arterial:

Weight-based regimen: 0.001 to 0.02 mg/kg/hour (maximum dose: 2 mg/hour) (Semba 2000)

or

Fixed-dose regimen: 0.12 to 2 mg/hour (Semba 2000)

Note: The ACC/AHA guidelines state that thrombolysis is an effective and beneficial therapy for those with acute limb ischemia (Rutherford categories I and IIa) of <14 days duration (Hirsch 2006). The optimal dosage and concentration has not been established; a number of intra-arterial delivery techniques are employed with continuous infusion being the most common (Ouriel 2004). The Advisory Panel to the Society for Cardiovascular and Interventional Radiology on Thrombolytic Therapy recommends dosing of ≤2 mg/hour and concomitant administration of subtherapeutic heparin (aPTT 1.25 to 1.5 times baseline) (Semba 2000). Duration of alteplase infusion dependent upon size and location of the thrombus; typically between 6 to 48 hours (Disini 2008).

Frostbite (off-label use): Note: For use in patients with deep frostbite injury with potential significant morbidity (eg, extending proximally to the proximal interphalangeal joints of digits), without contraindications to the use of alteplase, who present within 24 hours of injury. Use of alteplase in the field is not recommended; administer treatment in a facility capable of intensive-care monitoring (WMS [McIntosh 2014]). Additional data may be necessary to further define the role of alteplase in the treatment of frostbite.

Intra-arterial: 2 to 4 mg bolus followed by a continuous intra-arterial infusion of 0.5 to 1 mg/hour (total dose if bilateral extremity involvement) via femoral or brachial artery; administer with continuous infusion heparin via an intra-arterial catheter. Discontinue alteplase if fibrinogen levels decrease to <150 mg/dL, if reperfusion is complete (as evidenced by angiography), or after a period of 48 hours whether or not reperfusion is achieved (Bruen 2007; Ibrahim 2015).

Parapneumonic effusions and empyema (off-label use): Intrapleural: 10 mg (diluted in 30 mL of normal saline) administered twice daily for a total of 3 days; each alteplase dose was followed >2 hours later by an intrapleural dornase alfa dose (with a 1-hour dwell time for each drug) (Rahman 2011). Some clinicians suggest consideration of fibrinolytic use in patients in whom treatment with at least 24 hours of chest tube drainage has failed and who are poor surgical candidates (Hamblin 2010). Dosing for this indication has not been established. Alteplase monotherapy dosing regimens have varied (range: 10 to 100 mg) and produced conflicting results in small trials and case series. These regimens have also included variations in chest tube sizes, number of doses, patient positions (still vs rotation), and clamping durations (Thommi 2007; Thommi 2012).

Prosthetic valve thrombosis, right-sided (any size thrombus) or left-sided (thrombus area <0.8 cm2, recent onset [<14 days] of NYHA class I to II symptoms), or left-sided (thrombus area ≥0.8 cm2) when contraindications to surgery exist (off-label use) (ACCP [Guyatt 2012]; AHA/ACC [Nishimura 2014]; Alpert 2003; Roudaut 2003): IV:

High-dose regimen: Load with 10 mg, followed by 90 mg over 90 to 180 minutes (without heparin during infusion)

Low-dose regimen (preferred for very small adults): Load with 20 mg, followed by 10 mg/hour for 3 hours (without heparin during infusion)

Note: After successful administration of alteplase, heparin infusion should be introduced until warfarin achieves therapeutic INR (aortic: 3.0 to 4.0; mitral: 3.5 to 4.5) (Bonow 2008). The 2012 ACCP guidelines for antithrombotic therapy make no recommendation regarding INR range after prosthetic valve thrombosis.

Pulmonary embolism (PE) (submassive) (off-label use): Activase: IV: 100 mg over 2 hours; administered as a 10 mg bolus followed by 90 mg over 2 hours (Konstantinides 2002). Institute or resume parenteral anticoagulation near the end of or immediately following the alteplase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less. Note: Not recommended for submassive PE with minor RV dysfunction, minor myocardial necrosis, and no clinical worsening or low-risk PE (ie, normotensive, no RV dysfunction, normal biomarkers) (AHA [Jaff 2011]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Central venous catheter clearance: Intracatheter:

Patients <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg/2 mL; retain in catheter for 0.5 to 2 hours; may instill a second dose if catheter remains occluded

Patients ≥30 kg: 2 mg/2 mL; retain in catheter for 0.5 to 2 hours; may instill a second dose if catheter remains occluded

Parapneumonic effusions and empyema (off-label use): Infants >3 months, Children, and Adolescents: Intrapleural: 4 mg (diluted in 40 mL of normal saline), with the first dose administered at time of chest tube placement (with a 1-hour dwell time); repeat every 24 hours for a total of 3 doses; or 0.1 mg/kg (maximum: 3 mg) (diluted in 10 to 30 mL of normal saline), with the first dose administered after pigtail catheter (chest tube) placement (45- to 60-minute dwell time) and repeat doses administered every 8 hours for 3 days (total of 9 doses) (Bradley 2011; Hawkins 2004; St Peter 2009). Dosing for this indication has not been established. Several intrapleural dosage regimens have been evaluated and have included variations in chest tube sizes, number of doses, patient positions (still vs rotation), and clamping durations.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. Plasma clearance is rapid and mediated primarily by the liver; therefore, degree of renal impairment is unlikely to influence elimination of alteplase. Hemostatic defects due to severe renal disease may increase the risk for bleeding.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. Plasma clearance is rapid and mediated primarily by the liver. Significant hepatic impairment and hemostatic defects due to severe hepatic disease may increase the risk for bleeding.

Reconstitution

Activase:

50 mg vial: Use accompanying diluent (50 mL vial of sterile water for injection); let stand undisturbed for several minutes to allow large bubbles to dissipate; mix by gentle swirling and/or slow inversion; do not shake. Vacuum is present in 50 mg vial. Final concentration: 1 mg/mL.

100 mg vial: Use transfer set with accompanying diluent (100 mL vial of sterile water for injection); let stand undisturbed for several minutes to allow large bubbles to dissipate; mix by gentle swirling; do not shake. No vacuum is present in 100 mg vial. Final concentration: 1 mg/mL.

Activase: ST-elevation MI: Accelerated infusion: Bolus dose may be prepared by one of three methods:

1) Removal of 15 mL reconstituted (1 mg/mL) solution from vial

2) Removal of 15 mL from a port on the infusion line after priming

3) Programming an infusion pump to deliver a 15 mL bolus at the initiation of infusion

Activase: Acute ischemic stroke: Bolus dose (10% of total dose) may be prepared by one of three methods:

1) Removal of the appropriate volume from reconstituted solution (1 mg/mL)

2) Removal of the appropriate volume from a port on the infusion line after priming

3) Programming an infusion pump to deliver the appropriate volume at the initiation of infusion

Cathflo Activase: Add 2.2 mL sterile water for injection to vial; let the vial stand undisturbed to allow large bubbles to dissipate. Mix by gently swirling until completely dissolved (complete dissolution should occur within 3 minutes); do not shake. Final concentration: 1 mg/mL.

Administration

Activase: ST-elevation MI or acute ischemic stroke: Administer bolus dose (prepared by one of three methods) over 1 minute followed by infusion.

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

50 mg vial: Either PVC bag or glass vial and infusion set

100 mg vial: Insert spike end of the infusion set through the same puncture site created by transfer device and infuse from vial

If further dilution is desired, may be diluted in equal volume of 0.9% sodium chloride or D5W to yield a final concentration of 0.5 mg/mL.

Cathflo Activase: Intracatheter: Instill dose into occluded catheter. Do not force solution into catheter. After a 30-minute dwell time, assess catheter function by attempting to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in patients ≥10 kg or 3 mL in patients <10 kg to remove Cathflo Activase and residual clots. Gently irrigate the catheter with NS. If catheter remains nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell time: 120 minutes) and reassess function. If catheter function is not restored, a second dose may be instilled.

Parapneumonic pleural effusions and empyemas (off-label use): Intrapleural: Instill dose into chest tube and clamp drain. Although the optimum dwell time has not been determined, clinical trials more often have used either a 45 minute (Hawkins 2004) or 1 hour (Rahman 2011; St. Peter 2009) dwell time; after dwell period, release clamp and connect chest tube to continuous suction.

Compatibility

Stable in NS, SWFI; incompatible with bacteriostatic water, LR

Y-site administration: Incompatible with bivalirudin, dobutamine, heparin, morphine.

Storage

Activase: Store intact vials at room temperature (not to exceed 30°C [86°F]), or under refrigeration at 2°C to 8°C (36°F to 46°F); protect from light. Store reconstituted solution at 2°C to 30°C (36°F to 86°F) and use within 8 hours. Discard any unused solution

Cathflo Activase: Store intact vials at 2°C to 8°C (36°F to 46°F); protect from light. Store reconstituted solution at 2°C to 30°C (36°F to 86°F) and use within 8 hours. Discard any unused solution.

Solutions of 0.5 mg/mL, 1 mg/mL, and 2 mg/mL in SWI retained ≥94% of fibrinolytic activity at 48 hours when stored at 2°C in plastic syringes; these solutions retained ≥90% of fibrinolytic activity when stored in plastic syringes at -25°C or -70°C for 7 or 14 days, thawed at room temperature and then stored at 2°C for 48 hours (Davis 2000). Solutions of 1 mg/mL in SWI were stable for 22 weeks in plastic syringes when stored at -30°C and for ∼1 month in glass vials when stored at -20°C; bioactivity remained unchanged for 6 months in propylene containers when stored at -20°C and for 2 weeks in glass vials when stored at -70°C (Generali 2001).

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Anticoagulants: Thrombolytic Agents may enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

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

Dabigatran Etexilate: Thrombolytic Agents may enhance the anticoagulant effect of Dabigatran Etexilate. Management: Carefully monitor for bleeding. Dabigatran Canadian labeling recommends avoiding use with thrombolytic agents. Consider avoiding alteplase treatment of acute ischemic stroke in patients receiving dabigatran (see full drug monograph for details). Monitor therapy

Desirudin: Thrombolytic Agents may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with thrombolytic agents prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Consider therapy modification

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

Limaprost: May enhance the adverse/toxic effect of Thrombolytic Agents. The risk for bleeding may be increased. Monitor therapy

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

Prostacyclin Analogues: Thrombolytic Agents may enhance the adverse/toxic effect of Prostacyclin Analogues. Specifically, the antiplatelet effects of prostacyclin analogues may lead to an increased risk of bleeding when combined with thrombolytic agents. Monitor therapy

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

Test Interactions

Altered results of coagulation and fibrinolytic activity tests

Adverse Reactions

As with all drugs which may affect hemostasis, bleeding is the major adverse effect associated with alteplase. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the dosage administered, concurrent use of multiple agents which alter hemostasis, and patient predisposition. Rapid lysis of coronary artery thrombi by thrombolytic agents may be associated with reperfusion-related atrial and/or ventricular arrhythmia. Note: Lowest rate of bleeding complications expected with dose used to restore catheter function.

1% to 10%:

Cardiovascular: Hypotension

Central nervous system: Fever

Dermatologic: Bruising (1%)

Gastrointestinal: GI hemorrhage (5%), nausea, vomiting

Genitourinary: GU hemorrhage (4%)

Hematologic: Bleeding (0.5% major, 7% minor: GUSTO trial)

Local: Bleeding at catheter puncture site (15.3%, accelerated administration)

<1% (Limited to important or life-threatening): Angioedema (orolingual), intracranial hemorrhage (0.4% to 0.87% when adult dose is ≤100 mg), retroperitoneal hemorrhage, pericardial hemorrhage, gingival hemorrhage, epistaxis, allergic reaction (anaphylaxis, anaphylactoid reactions, laryngeal edema, rash, and urticaria [<0.02%])

Additional cardiovascular events associated with use in STEMI: AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia/infarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema, asystole, ventricular tachycardia, bradycardia, ruptured intracranial AV malformation, seizure, hemorrhagic bursitis, cholesterol crystal embolization

Additional events associated with use in pulmonary embolism: Pulmonary re-embolization, pulmonary edema, pleural effusion, thromboembolism

Additional events associated with use in stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke

Warnings/Precautions

Concerns related to adverse effects:

• Arrhythmias: Coronary thrombolysis may result in reperfusion arrhythmias (eg, accelerated idioventricular rhythm) (Miller 1986).

• Bleeding: Internal bleeding (intracranial, retroperitoneal, gastrointestinal, genitourinary, respiratory) or external bleeding, especially at arterial and venous puncture, sites may occur (may be fatal). The total dose should not exceed 90 mg for acute ischemic stroke or 100 mg for acute myocardial infarction or pulmonary embolism. Doses ≥150 mg associated with significantly increased risk of intracranial hemorrhage compared to doses ≤100 mg. Bleeding risk is low. Monitor all potential bleeding sites; if serious bleeding occurs, the infusion of alteplase and any other concurrent anticoagulants (eg, heparin) should be stopped.

• Cholesterol embolization: Has been reported rarely in patients treated with thrombolytic agents; may present with livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, or rhabdomyolysis and can be fatal.

• Orolingual angioedema: Although typically mild and transient, orolingual angioedema has occurred during and up to 2 hours after alteplase infusion in patients treated for AIS and STEMI. The use of concomitant ACE inhibitors and strokes involving the insular and frontal cortex are associated with an increased risk (Foster-Goldman 2013). The manufacturer recommends monitoring patients during and for several hours after infusion for orolingual angioedema. If angioedema develops, discontinue the infusion and promptly institute appropriate therapy.

Disease-related concerns:

• Conditions that increase bleeding risk: For the following conditions, the risk of bleeding is higher with use of thrombolytics and should be weighed against the benefits of therapy: Recent major surgery or procedure (eg, CABG, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels), traumatic or prolonged (>10 minutes) CPR (ACCF/AHA [O’Gara 2013]), lumbar puncture within 10 days (ASRA [Horlocker 2012]), cerebrovascular disease, recent intracranial hemorrhage, recent gastrointestinal or genitourinary bleeding, recent trauma, hypertension (adults with systolic BP >175 mm Hg and/or diastolic BP >110 mm Hg), high likelihood of left heart thrombus (eg, mitral stenosis with atrial fibrillation), acute pericarditis, subacute bacterial endocarditis, hemostatic defects including ones caused by severe renal or hepatic dysfunction, significant hepatic dysfunction, advanced age, diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, septic thrombophlebitis or occluded AV cannula at seriously infected site and/or any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of location. In the treatment of AIS, according to the AHA/ASA 2016 scientific statement, alteplase use is recommended in patients with end-stage renal disease on hemodialysis who have a normal aPTT (very limited populations evaluated). Patients with an elevated aPTT may have an increased risk for hemorrhagic complications (AHA/ASA [Demaerschalk 2016]).

• ST-elevation myocardial infarction (STEMI): Appropriate use: Follow standard management for STEMI while infusing alteplase.

• Stroke: Appropriate use: Patients who present within 3 hours of stroke symptom onset should be treated with alteplase unless contraindications exist. A longer time window (3 to 4.5 hours after symptom onset) has been shown to be safe and efficacious for select individuals who meet ECASS III criteria (AHA/ASA [Jauch 2013]; AHA/ASA [Demaerschalk 2016]; Hacke 2008).

Concurrent drug therapy issues:

• Anticoagulants: Use with caution in patients receiving oral anticoagulants; increased risk of bleeding. According to the AHA/ASA 2013 guidelines, in the treatment of acute ischemic stroke (AIS) within 3 hours of symptom onset, the current use of oral anticoagulants producing an INR >1.7, direct thrombin inhibitors, or direct factor Xa inhibitors with elevated sensitive laboratory test are contraindications. However, alteplase may be administered to patients with AIS having received direct thrombin inhibitors (eg, dabigatran) or direct factor Xa inhibitors (eg, rivaroxaban) when sensitive laboratory tests (eg, aPTT, INR, platelet count, ECT, TT, or appropriate direct factor Xa activity assays) are normal or the patient has not received a dose of these agents for >2 days (assuming normal renal function). When treating AIS 3 to 4.5 hours after symptom onset, the use of alteplase should be avoided with current use of any oral anticoagulant regardless of INR (AHA/ASA [Jauch 2013]). However, according to the AHA/ASA 2016 scientific statement, when treating AIS 3 to 4.5 hours after symptom onset, the use of alteplase appears safe and may be beneficial for patients taking warfarin with an INR <1.7 (AHA/AHA [Demaerschalk 2016]). In the treatment of STEMI, adjunctive use of parenteral anticoagulants (eg, enoxaparin, heparin, or fondaparinux) is recommended to improve vessel patency and prevent reocclusion and may also contribute to bleeding; monitor for bleeding (ACCF/AHA [O’Gara 2013]).

• Aspirin: In the treatment of acute ischemic stroke, avoid aspirin for 24 hours following administration of alteplase; administration within 24 hours increases the risk of hemorrhagic transformation. According to the AHA/ASA 2016 scientific statement, alteplase is recommended for patients taking antiplatelet drug monotherapy or antiplatelet combination therapy (eg, aspirin and clopidogrel) before stroke on the basis that the benefit outweighs a possible small increased risk of symptomatic intracerebral hemorrhage (sICH) (AHA/AHA [Demaerschalk 2016]).

• Heparin or low molecular weight heparin: Concurrent heparin anticoagulation may contribute to bleeding. In the treatment of acute ischemic stroke, concurrent use of anticoagulants was not permitted during the initial 24 hours of the <3 hour window trial (NINDS 1995). The AHA/ASA does not recommend initiation of anticoagulant therapy within 24 hours of treatment with alteplase (AHA/ASA [Jauch 2013]). Initiation of SubQ heparin (≤10,000 units) or equivalent doses of low molecular weight heparin for prevention of DVT during the first 24 hours of the 3 to 4.5 hour window trial was permitted and did not increase the incidence of intracerebral hemorrhage (Hacke 2008). Alteplase use is not recommended for acute ischemic stroke in patients who have received a dose of LMWH (prophylactic or treatment doses) within the previous 24 hours (AHA/ASA [Demaerschalk 2016]). For acute PE, withhold heparin during the 2-hour infusion period.

Special populations:

• Elderly: Use with caution in patients with advanced age (eg, >75 years); increased risk of bleeding. In the treatment of acute ischemic stroke (within 3 to 4.5 hours after symptom onset), alteplase use in patients >80 years is considered an exclusion criteria (AHA/ASA [Jauch 2013]; Hacke 2008). However, according to the AHA/AHA 2016 scientific statement, alteplase use in patients >80 years with acute ischemic stroke presenting within 3 to 4.5 hours after symptom onset is safe and can be as effective as in younger patients (AHA/ASA [Demaerschalk 2016]).

• Pregnancy: Use with caution in pregnancy; increased risk of bleeding.

Dosage form specific issues:

• Cathflo Activase: When used to restore catheter function, use Cathflo cautiously in those patients with known or suspected catheter infections. Evaluate catheter for other causes of dysfunction before use. Avoid excessive pressure when instilling into catheter.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Administration: Intramuscular injections and nonessential handling of the patient should be avoided. Venipunctures should be performed carefully and only when necessary. Avoid internal jugular and subclavian venous punctures. If arterial puncture is necessary, use an upper extremity vessel that can be manually compressed.

• Appropriate use: Alteplase has not been shown to treat adequately underlying deep vein thrombosis in patients with PE. Consider the possible risk of re-embolization due to the lysis of underlying deep venous thrombi in this setting.

Monitoring Parameters

Acute ischemic stroke (AIS): Baseline: Neurologic examination, head CT (without contrast), blood pressure, CBC, aPTT, PT/INR, glucose. During and after initiation: In addition to monitoring for bleeding complications, the 2013 AHA/ASA guidelines for the early management of AIS recommends the following:

Perform neurological assessments every 15 minutes during infusion and every 30 minutes thereafter for the next 6 hours, then hourly until 24 hours after treatment.

If severe headache, acute hypertension, nausea, or vomiting occurs, discontinue the infusion and obtain emergency CT scan.

Measure BP every 15 minutes for the first 2 hours of initiation then every 30 minutes for the next 6 hours, then hourly until 24 hours after initiation of alteplase. Increase frequency if a systolic BP is ≥180 mm Hg or if a diastolic BP is ≥105 mm Hg; administer antihypertensive medications to maintain BP at or below these levels.

Obtain a follow-up CT scan at 24 hours before starting anticoagulants or antiplatelet agents.

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

Pulmonary embolism: Monitor BP and HR continually and for at least 24 hours after administration; assess invasive catheters hourly for bleeding (Smithburger 2013).

ST-elevation MI: Baseline: Blood pressure, serum cardiac biomarkers, CBC, PT/INR, aPTT. During and after initiation: Assess for evidence of cardiac reperfusion through resolution of chest pain, resolution of baseline ECG changes, preserved left ventricular function, cardiac enzyme washout phenomenon, and/or the appearance of reperfusion arrhythmias; assess for bleeding potential through clinical evidence of GI bleeding, hematuria, gingival bleeding, fibrinogen levels, fibrinogen degradation products, PT and aPTT.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. The risk of bleeding may be increased in pregnant women. Information related to alteplase use in pregnancy is limited (Leonhardt 2006; Li 2012) and most guidelines consider pregnancy to be a relative contraindication for its use (AHA/ASA [Jauch 2013]; AHA/ASA [Demaerschalk 2016]; Jaff 2011; O’Gara 2013). Alteplase should not be withheld from pregnant women in life-threatening situations but should be avoided when safer alternatives are available (Bates 2012; Leonhardt 2006; Li 2012; Vanden Hoek 2010).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), skin discoloration to blue, black, or purple, angina, severe dizziness, passing out, severe headache, severe muscle pain, severe abdominal pain, or catheter site pain or irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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