Activase / Cathflo Activase (Alteplase)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Acute ischemic stroke (AIS) | Adults presenting within 3 hours of symptom onset (FDA label); intracranial haemorrhage excluded by imaging | Monotherapy with concomitant supportive care | FDA Approved |
| Acute myocardial infarction (AMI) | Adults — for the reduction of mortality and reduction of the incidence of heart failure | With concomitant aspirin and heparin (accelerated regimen evidence) | FDA Approved |
| Acute massive pulmonary embolism (PE) | Adults with acute PE obstructing flow to a lobe or multiple lung segments, or with unstable haemodynamics | Monotherapy (anticoagulation initiated near end of infusion) | FDA Approved |
| Restoration of central venous access device function | Adults and paediatric patients with thrombotic catheter occlusion (Cathflo Activase formulation) | Intracatheter instillation | FDA Approved |
Alteplase is recombinant human tissue plasminogen activator (rt-PA), a 527-amino-acid serine protease produced by recombinant DNA technology. The complementary DNA used in its synthesis was originally obtained from a human melanoma cell line (per the FDA prescribing information). Two formulations are marketed in the United States: Activase (50 mg and 100 mg vials) for systemic intravenous fibrinolysis in stroke, MI, and pulmonary embolism, and Cathflo Activase (2 mg vial), a separately FDA-licensed product for restoration of function to occluded central venous access devices. Initial U.S. approval of Activase was 1987 (originally for AMI); the AIS indication was added in 1996. The AMI indication is limited by the FDA label, which notes that the risk of stroke may outweigh thrombolytic benefit in patients whose AMI puts them at low risk for death or heart failure.
AIS within the 3 to 4.5-hour window — the FDA-approved window remains 3 hours, but the 2019 AHA/ASA acute ischemic stroke guideline recommends IV alteplase 0.9 mg/kg between 3 and 4.5 hours after symptom onset for selected eligible patients (Class of Recommendation I, Level of Evidence B-R). Use beyond 3 hours is therefore standard of care in the United States but technically off-label per the FDA label. Evidence quality: high (ECASS III; subsequent meta-analyses).
AIS with unwitnessed onset (e.g., wake-up stroke) — the 2019 AHA/ASA guideline considers IV alteplase within 4.5 hours of stroke recognition reasonable for patients with unknown time of onset when MRI shows DWI-positive / FLAIR-negative mismatch (WAKE-UP trial). Evidence quality: moderate (single pivotal RCT and supportive meta-analyses).
AIS in the 4.5 to 9-hour window with imaging selection — the most recent AHA/ASA acute ischemic stroke guideline update introduces a Class IIa recommendation for IV thrombolysis between 4.5 and 9 hours from onset (or last known well) when advanced perfusion imaging shows salvageable tissue (EXTEND trial and pooled analyses). Verify the current recommendation at the time of practice. Evidence quality: moderate.
Submassive (intermediate-risk) pulmonary embolism — use in PE with right-ventricular dysfunction but preserved systemic blood pressure is off-label and individualised; the FDA indication is restricted to “massive” PE. The PEITHO trial (which tested tenecteplase, a related fibrinolytic, not alteplase) showed reduction in haemodynamic decompensation but increased major bleeding without overall mortality benefit. Evidence quality: moderate (extrapolated from class evidence).
Catheter-directed thrombolysis for peripheral arterial occlusion or extensive deep-vein thrombosis. Evidence quality: low to moderate.
Dosing
Alteplase dosing is indication-specific and weight-based for systemic use. Reconstitute Activase only with the supplied Sterile Water for Injection USP (no preservative) to a 1 mg/mL solution; further dilution to 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose is permitted. Do not mix with other medications. Reconstituted solution is stable at 2–30 °C for 8 hours.
| Clinical Scenario | Starting Dose | Maintenance / Infusion | Maximum Dose | Notes |
|---|---|---|---|---|
| Acute ischemic stroke — within 3 h of onset (FDA label) | 10% of total dose IV bolus over 1 min | Remaining 90% IV over 60 min | 0.9 mg/kg, max 90 mg | Confirm no intracranial haemorrhage on imaging before initiation; pretreatment BP must be < 185/110 mm Hg No aspirin / heparin / antiplatelet for first 24 h after infusion (AIS) |
| Acute ischemic stroke — 3 to 4.5 h (off-label, 2019 AHA/ASA Class I) | 10% of total dose IV bolus over 1 min | Remaining 90% IV over 60 min | 0.9 mg/kg, max 90 mg | Same dose as 0–3 h window per AHA/ASA; benefit is time-dependent — treat as soon as eligible Off-label per FDA but recommended by guidelines in selected patients |
| Acute MI — accelerated regimen, > 67 kg | 15 mg IV bolus | 50 mg over first 30 min, then 35 mg over next 60 min | 100 mg total over 90 min | Concomitant aspirin and IV heparin per pivotal evidence (GUSTO-I) Largely supplanted by primary PCI where timely PCI is available |
| Acute MI — accelerated regimen, ≤ 67 kg | 15 mg IV bolus | 0.75 mg/kg over first 30 min, then 0.50 mg/kg over next 60 min | 100 mg total | Weight-banded scaling so total dose does not exceed 100 mg Concomitant aspirin and IV heparin |
| Acute MI — 3-hour infusion, ≥ 65 kg | 6–10 mg IV bolus | 50–54 mg rest of 1st hour; 20 mg in 2nd hour; 20 mg in 3rd hour | 100 mg total | Older regimen retained as alternative when accelerated regimen not feasible |
| Acute MI — 3-hour infusion, < 65 kg | 0.075 mg/kg IV bolus | 0.675 mg/kg rest of 1st h; 0.25 mg/kg in 2nd h; 0.25 mg/kg in 3rd h | 1.25 mg/kg over 3 h | Total dose should not exceed 100 mg in any AMI regimen — 150 mg is associated with increased intracranial haemorrhage |
| Acute massive pulmonary embolism | No bolus | 100 mg IV over 2 hours | 100 mg | Initiate parenteral anticoagulation near the end of, or immediately after, infusion when aPTT or thrombin time returns to ≤ 2× normal Risk of reembolisation from underlying DVT |
| Catheter occlusion — adults and children ≥ 30 kg (Cathflo) | 2 mg in 2 mL instilled into occluded lumen | Dwell 30–120 min; aspirate to assess function | Up to 2 doses of 2 mg each | If function is not restored after 120 min, a second 2 mg dose may be instilled No safety / efficacy data above 2 mg per dose for this indication |
| Catheter occlusion — children < 30 kg (Cathflo) | 110% of internal lumen volume | Not to exceed 2 mg in 2 mL | Up to 2 doses | Dose calculated to fill the catheter lumen; do not over-pressurise — vigorous suction or excessive pressure can damage the catheter |
Population-Specific Considerations
| Population | Adjustment | Rationale |
|---|---|---|
| Geriatric (> 75 years) | No formal dose adjustment | FDA PI Section 8.5 notes age > 77 years was associated with increased ICH risk in AIS exploratory analyses; functional outcome remained favourable; AHA/ASA endorses use |
| Renal impairment | No specified adjustment | Clearance is hepatic; severe renal disease may increase bleeding risk via uraemic platelet dysfunction (precaution, not contraindication) |
| Hepatic impairment | Use with caution | Significant hepatic dysfunction is listed by the FDA PI Section 5.1 as a condition that increases bleeding risk; weigh against anticipated benefit |
| Pediatric AIS / AMI / PE | Not established | Per FDA PI Section 8.4, safety and effectiveness for systemic indications have not been established; institutional paediatric stroke protocols may apply off-label under specialist supervision |
Use only the bundled Sterile Water for Injection USP — bacteriostatic water inactivates the molecule. Slight foaming is expected; let the vial stand to allow bubbles to dissipate, do not shake. The 100 mg vial does not contain vacuum and uses the supplied transfer device; the 50 mg vial is vacuum-sealed (do not use if vacuum is absent). Do not add any other medication to the infusion line. For AIS, the 10% bolus can be drawn from a port on the primed infusion line, or the pump can be programmed to deliver the bolus volume at the start of infusion.
Three Genentech thrombolytics are commonly confused: Activase (alteplase 50 / 100 mg vials, systemic IV thrombolysis), Cathflo Activase (alteplase 2 mg vial, intracatheter only), and TNKase (tenecteplase, single IV bolus). The FDA has issued specific medication-error alerts about confusion between these products. Verify the product name, vial strength, and indication on every order.
Pharmacology
Mechanism of Action
Alteplase is a recombinant DNA-derived form of human tissue plasminogen activator — a 527-amino-acid serine protease. The complementary DNA used in its synthesis was originally obtained from a human melanoma cell line. Its activity is fibrin-enhanced: in the absence of fibrin, alteplase converts plasminogen to plasmin only minimally, but when bound to fibrin within a thrombus it catalyses local conversion of entrapped plasminogen to plasmin, initiating clot lysis. This relative fibrin specificity, compared with the older non-specific thrombolytic streptokinase, is the basis for its preferential local fibrinolytic effect. Clinically meaningful systemic fibrinogen depletion still occurs, however: a 16–36% reduction in circulating fibrinogen has been described after a 100 mg dose, and approximately 11% of patients receiving 1.25 mg/kg over 3 hours had fibrinogen fall below 100 mg/dL in a controlled trial. The downstream plasmin then degrades fibrin and other coagulation factors, restoring vessel patency.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | IV administration only — no oral bioavailability (large glycoprotein); reconstituted to 1 mg/mL or further diluted to 0.5 mg/mL | Bolus and infusion can be given peripherally; do not co-infuse with other drugs in the same line |
| Distribution | Initial volume of distribution ≈ plasma volume; binds locally to fibrin within thrombus | Action is concentrated at the clot rather than uniformly systemic; basis for relative fibrin specificity |
| Metabolism | Predominantly hepatic clearance; degraded as a protein | Significant hepatic dysfunction increases bleeding risk and warrants caution |
| Elimination | Initial plasma half-life < 5 minutes in AMI patients (per FDA PI Section 12.3); plasma clearance 380–570 mL/min | Rapid disappearance from plasma drives bolus + short-infusion regimens; biologic effect (lysis, fibrinogen depletion, bleeding risk) outlasts measurable plasma drug |
Alteplase clears from plasma in minutes, but the systemic lytic state — depleted fibrinogen, plasmin-degraded coagulation factors, and impaired haemostasis — can persist for hours to days. The FDA prescribing information notes that haemorrhage can occur one or more days after Activase administration, particularly when patients also receive heparin or aspirin. This is the rationale for delaying additional antithrombotics for 24 hours after AIS thrombolysis.
Side Effects
The FDA prescribing information identifies bleeding as the most frequent adverse reaction across all approved indications. The incidence and clinical significance differ markedly by indication and dose: intracranial haemorrhage dominates the AIS risk profile, gastrointestinal and genitourinary bleeding dominate the AMI / PE profile, and Cathflo Activase (2 mg intracatheter) has shown a very low rate of serious adverse events in registration trials. The figures below are drawn directly from FDA PI Tables 3, 4, and 5.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Total intracranial haemorrhage (AIS, in-trial follow-up) | 15.4% | Placebo 6.4% (p < 0.01); pooled n = 624 from FDA PI Table 3 (NINDS rt-PA Stroke Studies 1 and 2) |
| All-cause 90-day mortality (AIS) | 17.3% | Placebo 20.5% (p = 0.36); not increased by alteplase despite the ICH excess |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Symptomatic ICH (AIS, in-trial follow-up) | 8.0% | Placebo 1.3% (p < 0.01); per FDA PI Table 3 |
| Asymptomatic ICH (AIS) | 7.4% | Placebo 5.1% (p = 0.32); detected on routine repeat CT without clinical worsening |
| Symptomatic ICH within 36 hours (AIS) | 6.4% | Placebo 0.6% (p < 0.01); the early window in which most clinically relevant ICH occurs |
| Bleeding requiring red-cell transfusion (AIS) | 6.4% | Placebo 3.8% (p = 0.19); reflects the systemic bleeding profile in the AIS cohort |
| New ischemic stroke at 3 months (AIS) | 5.8% | Placebo 5.4% (p = 1.00); not increased by alteplase |
| Gastrointestinal bleeding (AMI 3-h regimen) | 5% | Per FDA PI Table 4; total dose ≤ 100 mg; n > 800 |
| Genitourinary bleeding (AMI 3-h regimen) | 4% | Per FDA PI Table 4 |
| Ecchymosis (AMI 3-h regimen) | 1% | Particularly at puncture sites; minimise venipunctures |
| Retroperitoneal, epistaxis, gingival bleeding (AMI 3-h regimen) | < 1% each | Per FDA PI Table 4 |
| Intracranial haemorrhage (AMI 3-h, 100 mg) | 0.4% | n = 3,272 per FDA PI Table 5 |
| Intracranial haemorrhage (AMI accelerated, ≤ 100 mg) | 0.7% | n = 10,396 per FDA PI Table 5 |
| Intracranial haemorrhage (AMI, 150 mg) | 1.3% | n = 1,779; this is the rationale that 150 mg should not be used for AMI |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Symptomatic intracranial haemorrhage (AIS) | 8.0% in AIS pivotal cohort; 6.4% within 36 h | Usually first 24–36 h | Stop infusion; urgent CT; cryoprecipitate ± antifibrinolytic (tranexamic acid or aminocaproic acid); platelet transfusion if low or on antiplatelet; neurosurgery consult |
| Major systemic bleeding (any indication) | Increased over baseline; specific rate varies by site (see Common Bleeding table) | During infusion or within 24 h; can occur days later if anticoagulated | Stop infusion immediately; pressure on compressible sites; cryoprecipitate; transfusion as needed |
| Orolingual angioedema | Reported during and up to 2 h after infusion (AIS / AMI); higher risk with concomitant ACE inhibitors | During or within 2 h of infusion | Stop infusion; airway assessment; antihistamines, IV corticosteroids, epinephrine; intubate early if airway compromised (avoid traumatic intubation — fatal haemorrhage reported) |
| Anaphylactoid / allergic reactions | Reported (frequency not quantified in PI) | Any time during infusion | Discontinue; standard anaphylaxis management |
| Cholesterol embolisation | Rare; true incidence unknown | Days after exposure | Recognise (livedo reticularis, “purple toe”, AKI, gangrenous digits, pancreatitis); supportive care; can be fatal |
| Pulmonary reembolisation | Reported in PE patients; lysis of underlying DVT may release further emboli | During or after infusion | Anticoagulation as soon as aPTT or thrombin time permits; supportive haemodynamic care |
| Cardiac complications (post-marketing, AMI) | Reported; frequency confounded by underlying AMI | During or after AMI | Recognise arrhythmia, AV block, cardiogenic shock, myocardial rupture, pericardial effusion, tamponade — manage per acute MI protocol |
| AIS post-marketing CNS events | Reported (frequency not quantifiable) | During or after infusion | Cerebral oedema, cerebral herniation, seizure, new ischemic stroke — manage per neurocritical care protocol; can be life-threatening |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Suspected intracranial haemorrhage | Per protocol | Sudden clinical worsening (deteriorating LOC, new headache, vomiting, BP surge) → stop infusion, urgent CT |
| Major extracranial bleeding | Per protocol | Stop infusion, apply pressure to compressible sites, supportive transfusion |
| Orolingual angioedema | Per protocol | Stop infusion immediately, secure airway, treat with antihistamines / corticosteroids / epinephrine |
| Pretreatment INR > 1.7 or aPTT elevated (AIS) | Per protocol | Per FDA PI Section 2.1 — discontinue if results return after initiation in patients without recent anticoagulant use |
If a patient receiving alteplase develops sudden neurological deterioration, severe headache, acute hypertension, nausea or vomiting: stop the infusion, secure the airway and IV access, and obtain an urgent non-contrast CT. While imaging is pending, send fibrinogen, platelets, PT / aPTT, and type and crossmatch. If ICH is confirmed, administer cryoprecipitate (typically 10 units; target fibrinogen ≥ 150 mg/dL), consider an antifibrinolytic (tranexamic acid 1 g IV or aminocaproic acid), correct platelets if needed, and consult neurosurgery and haematology promptly. Reversal protocols vary by institution — follow local guidance.
Drug Interactions
Formal drug-interaction studies of alteplase with other cardioactive or cerebroactive drugs have not been conducted. The FDA prescribing information explicitly addresses two interaction categories: antithrombotic drugs (additive bleeding risk) and angiotensin-converting enzyme inhibitors (post-marketing reports of orolingual angioedema). Several additional clinically important interactions are based on shared bleeding mechanisms and are reflected in major reference databases (Lexicomp, Micromedex).
The FDA prescribing information cautions that coagulation tests and measures of fibrinolytic activity may be unreliable during alteplase therapy because circulating drug remains active in vitro and can degrade fibrinogen in blood samples after collection. Specific precautions (rapid sample handling and inhibitor addition) are required for accurate post-treatment fibrinogen measurement.
Monitoring
Alteplase requires intensive bedside monitoring during and after infusion. The dominant priorities are early detection of bleeding (especially intracranial), tight blood-pressure control, and airway assessment for angioedema. AHA/ASA stroke guidelines specify a structured neurological- and BP-monitoring schedule for the first 24 hours after AIS thrombolysis, summarised below.
-
Blood Pressure (AIS)
Every 15 min × 2 h, then q 30 min × 6 h, then q 60 min × 16 h
Routine Goal < 180/105 mm Hg for the first 24 h after AIS thrombolysis (AHA/ASA). Treat with IV labetalol, nicardipine, or clevidipine per institutional protocol. Pretreatment BP must be < 185/110 mm Hg before the bolus. -
Neurological Exam
Same schedule as BP for first 24 h
Routine NIHSS or focused neurological check; any acute deterioration mandates immediate stop of infusion and urgent CT to exclude ICH. -
Bleeding Surveillance
Continuous during infusion; clinical monitoring ≥ 24 h
Routine Inspect arterial puncture sites, mucous membranes, urine, and stool. Avoid IM injections, urinary catheters, NG tubes, and central venous access during the first 24 h unless essential. -
Airway / Angioedema
During and for ≥ 2 h after infusion
Routine Inspect tongue and oropharynx, especially in patients on ACE inhibitors. Have antihistamines, corticosteroids, and epinephrine available. -
Cardiac Rhythm (AMI)
Continuous telemetry
Routine Watch for reperfusion arrhythmias, AV block, hypotension; recognise mechanical complications (rupture, tamponade) early. -
Repeat CT (AIS)
At 24 h or sooner if deterioration
Routine Required before initiating antiplatelet or anticoagulant therapy; sooner if any neurological worsening, severe headache, or BP surge. -
Coagulation Panel
Baseline; repeat with bleeding
Trigger-based Pretreatment INR (must be ≤ 1.7 for AIS per FDA PI), aPTT, platelets, fibrinogen, type and screen. In AIS without recent anticoagulant use, treatment can begin before results return; discontinue if INR > 1.7 or aPTT elevated. -
Glucose
At presentation in AIS
Trigger-based Hypoglycaemia (typically < 50 mg/dL) and severe hyperglycaemia can mimic stroke; the AHA/ASA guideline recommends correcting glucose abnormalities before treatment but does not categorically exclude eligible patients once glucose is corrected. -
Catheter Function (Cathflo)
At 30 min and 120 min after instillation
Routine Aspirate gently to test patency. If unsuccessful at 120 min, a second 2 mg dose may be instilled.
Contraindications & Cautions
Absolute Contraindications — Acute Ischemic Stroke (FDA PI Section 4.1)
- Current intracranial haemorrhage
- Subarachnoid haemorrhage
- Active internal bleeding
- Recent (within 3 months) intracranial or intraspinal surgery, or serious head trauma
- Intracranial conditions that may increase the risk of bleeding — e.g., some neoplasms, arteriovenous malformations, aneurysms
- Bleeding diathesis
- Current severe uncontrolled hypertension — generally interpreted clinically as BP that cannot be lowered to < 185/110 mm Hg with antihypertensives prior to thrombolysis
Absolute Contraindications — Acute MI or Pulmonary Embolism (FDA PI Section 4.2)
- Active internal bleeding
- History of recent stroke
- Recent (within 3 months) intracranial or intraspinal surgery, or serious head trauma
- Intracranial conditions that may increase the risk of bleeding
- Bleeding diathesis
- Current severe uncontrolled hypertension
Absolute Contraindication — Cathflo Activase
- Known hypersensitivity to alteplase or any formulation excipient
Relative Contraindications (Specialist Input Recommended)
The FDA PI Section 5.1 lists conditions in which the bleeding risks of Activase therapy for all approved indications are increased and should be weighed against the anticipated benefits. These include:
- Recent major surgery or procedure — coronary artery bypass graft, obstetric delivery, organ biopsy, previous puncture of non-compressible vessels
- Cerebrovascular disease
- Recent intracranial haemorrhage
- Recent gastrointestinal or genitourinary bleeding
- Recent trauma
- Hypertension — systolic BP above 175 mm Hg or diastolic BP above 110 mm Hg per the FDA PI; the AHA/ASA threshold for AIS is < 185/110 mm Hg before bolus
- High likelihood of left heart thrombus — e.g., mitral stenosis with atrial fibrillation
- Acute pericarditis
- Subacute bacterial endocarditis
- Hemostatic defects, including those secondary to severe hepatic or renal disease
- Significant hepatic dysfunction
- Pregnancy
- Diabetic haemorrhagic retinopathy or other haemorrhagic ophthalmic conditions
- Septic thrombophlebitis or occluded AV cannula at a seriously infected site
- Advanced age — increased ICH risk in AIS analyses (especially > 77 years), but functional benefit retained per AHA/ASA
- Patients currently receiving anticoagulants (e.g., warfarin)
- Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location
Use with Caution
- Concomitant ACE inhibitor — higher reported risk of orolingual angioedema; monitor airway during and after infusion.
- Pulmonary embolism with extensive proximal DVT — risk of reembolisation as the lytic state dissolves the source clot.
- Pediatric systemic use (AIS, AMI, PE) — safety and effectiveness not established per FDA PI Section 8.4; institutional paediatric stroke protocols may apply off-label under specialist supervision.
- Pregnancy — animal data show embryocidal effects; no adequate human data. Use only when clearly indicated and the benefit outweighs the unknown risk.
- Lactation — excretion in human milk unknown per FDA PI Section 8.3; risk-benefit decision based on the acuity of the indication.
Activase increases the risk of bleeding (intracranial, retroperitoneal, gastrointestinal, genitourinary, respiratory, or external — especially at puncture sites). Avoid intramuscular injections and minimise venipunctures. If serious bleeding occurs, terminate the infusion immediately. There is no FDA boxed warning on the Activase label, but the bleeding caution is the central theme of the prescribing information.
Orolingual angioedema has been reported during and up to 2 hours after Activase infusion, particularly in patients also receiving angiotensin-converting enzyme inhibitors. Monitor patients during and for several hours after infusion. If angioedema develops, discontinue Activase and treat with antihistamines, IV corticosteroids, and epinephrine; secure the airway early. Cholesterol embolism has rarely been reported with thrombolytics. Reembolisation from underlying deep vein thrombosis should be considered when treating PE.
Patient Counselling
Purpose of Therapy
Alteplase is an emergency, single-dose therapy. Most patients (or surrogate decision-makers) receive it under acute, time-pressured conditions for stroke, heart attack, or major pulmonary embolism. Counselling typically occurs in two phases: a brief consent conversation before the infusion (when feasible) covering the trade-off between potential benefit and bleeding risk, and a more thorough post-infusion conversation about ongoing observation, recovery, and follow-up. For Cathflo Activase used to clear an occluded venous catheter, counselling focuses on the procedural nature of the dose and what to expect.
Before the Infusion (where time permits)
Explain in plain language that the medicine works by dissolving the clot blocking a brain artery, heart artery, or major lung vessel. Earlier treatment increases the chance of a good outcome. The most important risk is bleeding — including bleeding into the brain, which in stroke trials occurred symptomatically in around 8 of every 100 patients treated, and which can be fatal in some cases. Despite this risk, the trial evidence shows that more patients return to independent living than would without the medicine. Allergic reactions, including swelling of the tongue and lips, are uncommon but possible, especially in patients on certain blood-pressure medicines.
Sources
- Activase® (alteplase) US Prescribing Information. Genentech, Inc. Revised February 2015. accessdata.fda.gov Primary FDA label for systemic Activase; source for indications, dosing, contraindications, and adverse-reaction tables (Tables 3, 4, 5) and pharmacokinetic values cited throughout this monograph.
- Cathflo® Activase® (alteplase) US Prescribing Information. Genentech, Inc. accessdata.fda.gov Separate FDA label for the 2 mg intracatheter formulation, including the paediatric weight-based instillation rule.
- The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. doi.org/10.1056/NEJM199512143332401 Pivotal NINDS trial that established alteplase efficacy in AIS within 3 hours; source of the 3-month outcome data summarised in FDA PI Table 7.
- Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329. doi.org/10.1056/NEJMoa0804656 ECASS III — pivotal evidence supporting the 3 to 4.5-hour extended treatment window adopted by AHA/ASA guidelines.
- The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329(10):673-682. doi.org/10.1056/NEJM199309023291001 GUSTO-I — pivotal accelerated-infusion AMI trial (n = 41,021) referenced in FDA PI Table 8.
- Thomalla G, Simonsen CZ, Boutitie F, et al; WAKE-UP Investigators. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379(7):611-622. doi.org/10.1056/NEJMoa1804355 Imaging-selection trial supporting the wake-up / unwitnessed-onset stroke recommendation.
- Ma H, Campbell BCV, Parsons MW, et al; EXTEND Investigators. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380(19):1795-1803. doi.org/10.1056/NEJMoa1813046 EXTEND — extended-window evidence underpinning the 4.5–9 h Class IIa recommendation in subsequent AHA/ASA guideline updates.
- Meyer G, Vicaut E, Danays T, et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411. doi.org/10.1056/NEJMoa1302097 PEITHO tested tenecteplase, not alteplase, but is the most-cited contemporary evidence on fibrinolysis for intermediate-risk PE — informs the off-label submassive PE discussion only as class-level evidence.
- Blaney M, Shen V, Kerner JA, et al; CAPS Investigators. Alteplase for the treatment of central venous catheter occlusion in children: results of a prospective, open-label, single-arm study (Cathflo Activase Pediatric Study). J Vasc Interv Radiol. 2006;17(11 Pt 1):1745-1751. pubmed.ncbi.nlm.nih.gov/17142704 Paediatric Cathflo Activase efficacy and safety dataset supporting the < 30 kg dosing rule.
- Powers WJ, Rabinstein AA, Ackerson T, et al; American Heart Association Stroke Council. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke. Stroke. 2019;50(12):e344-e418. doi.org/10.1161/STR.0000000000000211 2019 AHA/ASA AIS guideline update — basis for the 3 to 4.5-hour Class I recommendation, the wake-up stroke recommendation, and post-thrombolysis BP targets cited in the monitoring section.
- American Heart Association / American Stroke Association. Most recent guideline for the early management of patients with acute ischemic stroke (published 2025/2026). Stroke. ahajournals.org/journal/str Most recent AHA/ASA AIS guideline introducing the 4.5–9 h Class IIa extended-window recommendation and equivalence statement for tenecteplase 0.25 mg/kg vs alteplase 0.9 mg/kg. Confirm the published citation (authors, journal, year, DOI) at time of publication.
- O’Gara PT, Kushner FG, Ascheim DD, et al; American College of Cardiology Foundation / American Heart Association Task Force. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol. 2013;61(4):e78-e140. doi.org/10.1016/j.jacc.2012.11.019 ACC/AHA STEMI guideline — context for fibrinolytic therapy when timely PCI is not available.
- Konstantinides SV, Meyer G, Becattini C, et al; The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2020;41(4):543-603. doi.org/10.1093/eurheartj/ehz405 ESC PE guideline — defines high-risk (massive) and intermediate-risk PE and the role of systemic thrombolysis.
- Pennica D, Holmes WE, Kohr WJ, et al. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature. 1983;301(5897):214-221. doi.org/10.1038/301214a0 Original cloning paper that enabled recombinant production of human t-PA — historical foundation for the molecule.
- Activase® (alteplase) US Prescribing Information, Section 12.3 (Pharmacokinetics). Genentech, Inc. accessdata.fda.gov Primary source for the initial half-life (< 5 minutes), plasma clearance (380–570 mL/min), volume of distribution (~ plasma volume), and hepatic clearance described in this monograph.
- Alteplase. Drugs and Lactation Database (LactMed®). National Library of Medicine, Bethesda (MD). ncbi.nlm.nih.gov/books/NBK500827 Lactation safety summary — confirms human milk excretion data are not available; informs the cautions in this monograph.