Alteplase is a parenteral tissue plasminogen activator (tPA) indicated for the treatment of acute ischemic stroke, acute myocardial infarction to reduce mortality and incidence of heart failure, and acute massive pulmonary embolism for lysis, and for the restoration of function to central venous access devices as assessed by the ability to withdraw blood. When used for acute myocardial infarction, the risk of stroke may be greater than the benefit in patients at low risk of death from cardiac causes. Alteplase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites; hemorrhage can occur 1 or more days after administration of alteplase. The use of thrombolytics can increase the risk of thromboembolic events in patients with a high likelihood of left heart thrombus. Also, cholesterol embolism has been reported rarely in patients treated with thrombolytic agents.
Updates for coronavirus disease 2019 (COVID-19):
Available data are limited and efficacy has not been established. Due to a lack of clinical data, the National Institutes of Health (NIH) COVID-19 treatment guidelines do not give recommendations for or against the use of thrombolytics, such as alteplase. In a case series (n = 3) of critically ill patients with acute respiratory distress syndrome (ARDS) and respiratory failure given alteplase, an initial improvement in PaO2/FiO2 (P/F) ratio ranging from 11% to 100% was observed in all 3 patients; however, improvements were transient. Heparin was initiated or resumed immediately after the completion of alteplase infusion without bleeding complications. Redosing and/or using a higher bolus dose (50 to 100 mg) without holding anticoagulation is postulated that may provide a more durable response. Additional data regarding clinical efficacy for COVID-19 are being evaluated.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Reconstitution
-Reconstitute only with the provided Sterile Water for Injection to a final concentration of 1 mg/mL.
-50-mg vials: Do not use if the vacuum is not present. Using a large-bore needle (e.g., 18-gauge) and a syringe, add the accompanying Sterile Water for Injection to the alteplase vial. Direct the stream of water into the lyophilized cake.
-100-mg vials: Vials do not contain a vacuum. With the vial of Sterile Water for Injection upright, insert the piercing pin of the transfer device (provided) vertically into the center of the stopper. Hold the vial of alteplase upside-down over the piercing pin of the transfer device and push down so that the piercing pin is inserted through the center of the vial stopper. Invert the 2 vials so that the vial of alteplase is on the bottom and allow the diluent to flow down through the transfer device; about 0.5 mL of Sterile Water for Injection will remain in the diluent vial. Remove the transfer device and diluent vial from the alteplase vial and discard. Swirl gently to dissolve the powder. DO NOT SHAKE.
-Slight foaming is not unusual after reconstitution; let the solution stand undisturbed for several minutes to allow large bubbles to dissipate.
-Storage: Use within 8 hours of reconstitution.
Dilution
-Alteplase may be administered as the reconstituted 1 mg/mL solution or further diluted immediately prior to administration in an equal volume of 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration of 0.5 mg/mL. Polyvinyl chloride bags or glass vials are acceptable for dilution.
-ASHP Recommended Standard Concentrations for Adult Continuous Infusions: 1 mg/mL.
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 1 mg/mL.
Bolus Dose Preparation
-The bolus dose may be prepared in 1 of the following ways:-Remove the appropriate volume from the reconstituted (1 mg/mL) vial using a syringe and needle. If this method is used with 50-mg vials, the syringe should not be primed with air and the needle should be inserted into the vial stopper. If the 100-mg vial is used, the needle should be inserted away from the puncture mark made by the transfer device.
-Remove the appropriate indication-specific volume from a port (second injection site) on the infusion line after the infusion set is primed.
-Program an infusion pump to deliver the appropriate indication-specific volume as a bolus at the initiation of the infusion.
IV Infusion
-50-mg vials: Administer using a polyvinyl chloride bag or glass vial and infusion set.
-100-mg vials: Remove from the vial the amount of drug that is not needed for the indication-specific dose for the patient. Insert the spike end of an infusion set through the same puncture site created by the transfer device in the stopper of the vial of reconstituted alteplase. Hang the reconstituted vial from the clear plastic hanger attached to the vial label.
-Length of infusion depends upon indication.
-If extravasation occurs, terminate the infusion at that site and apply local therapy.
Other Injectable Administration
Central Venous Catheter Instillation Administration
-Alteplase is instilled into the occluded lumen of a central venous catheter.
-Consider other reasons for catheter dysfunction, such as catheter malposition, mechanical failure, constriction by a suture, and lipid deposits or drug precipitates within the lumen, before treatment with alteplase.
-Avoid vigorous suction during attempts to determine catheter occlusion to prevent damage to the vascular wall or collapse of soft-walled catheters.
-Avoid excessive pressure when alteplase is instilled into the catheter. Such force could cause rupture of the catheter or expulsion of the clot into the circulation.
Reconstitution
-Aseptically withdraw 2.2 mL Sterile Water for Injection. Do not use Bacteriostatic Water for Injection.
-Inject the 2.2 mL of Sterile Water for Injection into the vial, directing the diluent stream into the powder. Slight foaming is not unusual; let the vial stand undisturbed to allow large bubbles to dissipate.
-Mix gently by swirling until the contents completely dissolve. Complete dissolution should occur within 3 minutes. DO NOT SHAKE. The reconstituted product results in a colorless to pale yellow clear solution containing 1 mg/mL alteplase at a pH of about 7.3.
-Storage: Use immediately after reconstitution. The solution may be used for intracatheter instillation within 8 hours following reconstitution when stored at 2 to 30 degrees C (36 to 86 degrees F).
-No other medication should be added to solutions containing alteplase.
Cryopreserved Bolus Injection Preparation
NOTE: Alteplase is not FDA-approved to be prepared as cryopreserved bolus injections.
-In vitro data support that cryopreserved alteplase solutions maintain bioactivity in propylene syringes for 6 months and in glass vials for 2 weeks. Using aseptic technique, dilute alteplase to a concentration of 1 mg/mL.-For propylene syringes: Withdraw 1 mL into polypropylene syringes and cryopreserve at -20 degrees C. Aliquots retain bioactivity for 6 months.
-For glass vials: Withdraw 2 mL into glass vials and cryopreserve at -70 degrees C for 2 weeks; then, thaw and maintain at 22 to 24 degrees C for 24 hours; then, store at -70 degrees C for up to 19 days.
Intracatheter Instillation
-Withdraw 2 mL (2 mg) of solution from the reconstituted vial.
-Instill the appropriate dose into the occluded catheter.
-After 30 minutes of dwell time, assess catheter function by attempting to aspirate blood.
-If the catheter is not functional after 30 minutes, allow the solution to remain for an additional 90 minutes (120 minutes of total dwell time) and assess catheter function by attempting to aspirate blood and catheter contents.
-If catheter function is not restored after 120 minutes, a second dose may be instilled. After instillation of second dose, check catheter function 30 minutes and, if needed, 120 minutes after second instillation.
-If catheter function is restored, aspirate 4 to 5 mL of blood in patients weighing 10 kg or more or 3 mL in patients weighing less than 10 kg to remove alteplase and residual clot. Gently irrigate the catheter with 0.9% Sodium Chloride Injection.
-Discard any unused solution.
Intrapleural Catheter Administration*
Preparation
-Dilute 2 to 10 mg in a sufficient amount of 0.9% Sodium Chloride Injection. Multiple concentrations have been used.
--2 mg has been diluted with 20 mL of 0.9% Sodium Chloride Injection.
-3 mg has been diluted with 10 to 20 mL of 0.9% Sodium Chloride Injection.
-4 mg has been diluted with 10 to 50 mL of 0.9% Sodium Chloride Injection.
-10 mg has been diluted with 30 mL of 0.9% Sodium Chloride Injection.
Intrapleural Instillation
-Inject via chest tube followed by 5 mL 0.9% Sodium Chloride flush and clamp chest tube for 1 hour, then allow to drain for 1 hour.
Bleeding associated with alteplase therapy can be divided into 2 broad categories. Internal bleeding includes intracranial bleeding (0.4% to 15.4%), retroperitoneal bleeding (less than 1%), GI bleeding (5%), genitourinary bleeding (4%), and respiratory bleeding. Superficial or surface bleeding is observed mainly at invaded or disturbed sites such as venous cutdowns, arterial punctures, and sites of recent surgical intervention. Less serious spontaneous bleeding includes ecchymosis (1%), gingival bleeding (less than 1%), and epistaxis (less than 1%). In clinical studies of adults with acute ischemic stroke (n = 624), a higher incidence of intracranial bleeding (15.4% vs. 6.4%), especially symptomatic intracranial bleeding (8% vs. 1.3%), was seen in patients receiving alteplase compared to placebo. However, there was no increase in the incidence of 90-day mortality or severe disability in patients receiving alteplase. Studies indicate that the incidence of intracranial bleeding is dose-related (150 mg, 1.3% vs. 100 mg, 0.4%). Doses more than 0.9 mg/kg may be associated with an increased incidence of intracranial hemorrhage. The frequency of bleeding requiring blood transfusions was 6.5% for alteplase-treated patients vs. 3.8% of patients given placebo in clinical trials (p = 0.19). Bleeding occurs most commonly at access sites, such as catheter insertion sites or venipuncture sites. During clinical trials with alteplase for catheter occlusion, 3 patients had a major GI bleed 2 to 3 days after alteplase treatment. A case of injection site hemorrhage was observed 4 hours after alteplase treatment in a patient with pre-existing thrombocytopenia. These events may have been related to underlying disease and treatments for malignancy, but a contribution to alteplase to these events cannot be ruled out. There have been no reports of intracranial hemorrhage with alteplase use for occluded catheters. If serious or severe bleeding occurs during therapy, promptly discontinue alteplase. Medical management of spontaneous intracerebral hemorrhage in patients with severe factor deficiency or thrombocytopenia should include factor replacement therapy or platelets, respectively. Treatment of intracerebral hemorrhage related to alteplase is largely supportive. Fresh frozen plasma, cryoprecipitate, platelets, phytonadione, aminocaproic acid, and tranexamic acid have been used in the treatment of intracerebral hemorrhage after alteplase administration. Guidelines recommend tranexamic acid or aminocaproic acid for the management of symptomatic intracranial bleeding occurring within 24 hours after alteplase administration for the treatment of acute ischemic stroke. There is potential for benefit in all patients, but particularly when blood products are contraindicated or declined by patient/family or if cryoprecipitate is not available in a timely manner.
Rapid coronary lysis can result in the development of cardiac arrhythmias. Arrhythmias that have been observed include sinus bradycardia, accelerated idioventricular rhythm, premature ventricular contractions (PVCs), and ventricular tachycardia. In general, these adverse reactions are secondary to clot lysis and subsequent reperfusion of ischemic areas and not directly attributable to alteplase therapy. It is recommended that antiarrhythmic therapy for bradycardia and or ventricular irritability be available when alteplase is administered.
Nausea, vomiting, and fever have been reported during administration of alteplase, but it is uncertain if these adverse reactions are associated with the underlying disease or are attributable to alteplase.
Cholesterol microembolization has been reported rarely in patients receiving thrombolytic agents (e.g., alteplase); the true incidence is unknown. This condition, which can be fatal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, or vascular surgery) and/or anticoagulant therapy. Clinical features include livedo reticularis such as 'purple toe syndrome', acute renal failure, gangrenous digitus, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, or rhabdomyolysis.
Infection after use of alteplase for central venous catheter occlusion has been reported including 4 catheter-related sepsis events occurring from 15 minutes to 1 day after treatment with alteplase, and a fifth sepsis event occurred on day 3 after alteplase treatment (n = 1,122). All 5 patients had positive catheter or peripheral blood cultures within 24 hours after symptom onset. In another study, 3 cases of sepsis occurred 2 to 44 hours after treatment; however, all of these patients had evidence of infection prior to alteplase administration. An additional patient developed signs of infection within 1 day of alteplase administration and required antibiotics.
Three cases (n = 1,122) of subclavian and upper extremity deep venous thrombosis were reported 3 to 7 days after alteplase treatment for catheter occlusion. These events may have been related to the underlying disease or long-term presence of an indwelling catheter, but a contribution to occurrence of the events from alteplase treatment cannot be ruled out. There have been no reports of pulmonary embolus.
Allergic-type reactions have been reported with the use of alteplase including rash, urticaria, laryngeal edema, orolingual angioedema, anaphylactoid reactions, and anaphylactic shock. A cause and effect relationship to alteplase has not been established. Angioedema primarily occurred in patients treated for acute ischemic stroke; however, angioedema was observed in some patients treated for acute myocardial infarction. The onset of angioedema occurred during and up to 2 hours after infusion of alteplase. In many cases, patients were receiving concomitant ACE inhibitors. Most cases resolved with prompt treatment; rare fatalities were associated with upper airway hemorrhage due to traumatic intubation. Monitor patients treated with alteplase during and for several hours after infusion for signs of hypersensitivity. If signs of hypersensitivity are noted, promptly discontinue alteplase and institute appropriate therapy (e.g., antihistamines, IV corticosteroids, H2-antagonists, epinephrine).
Stroke has been reported with the use of alteplase. In trials for the treatment of myocardial infarction in adults, using the accelerated infusion regimen, the incidence of all strokes was 1.6%, while the incidence of nonfatal stroke was 0.9%. Hemorrhagic stroke was reported in 0.7% of patients. The incidence increased with increasing age. Data from trials utilizing the 3-hour infusion indicated that the incidence of stroke was 1.2%. Early recurrent ischemic stroke has rarely been reported in patients receiving alteplase. In a retrospective study of 341 adult patients that received alteplase for acute stroke, 2 patients experienced early recurrent ischemic stroke (within 40 to 50 minutes after alteplase initiation) seen as ischemic lesions diagnosed by cranial computed tomography (CCT). While the occurrence of such a phenomenon is rare, clinicians should be aware that early deterioration in patients manifested as decreased consciousness, coma, and possibly convulsions, may be the result of recurrent ischemia rather than intracranial hemorrhage. The authors of this study stress the importance of discontinuing the thrombolytic as well as having the patient undergo an urgent CCT if a patient experiences early deterioration. If early recurrent ischemic stroke is suspected, patients should undergo further diagnostic evaluation (via diffusion- and perfusion-weighted MRI) to estimate the extent of ischemia. The results of the MRIs can determine management strategies.
Cerebral adverse events that may be associated with alteplase therapy for ischemic stroke include cerebral edema, cerebral herniation, and seizures, which may be life-threatening and lead to death.
Cardiovascular adverse events that may be associated with alteplase during treatment of myocardial infarction include AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia, myocardial reinfarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, and hypotension. Hypotension and thromboembolism have also been reported during treatment of pulmonary embolism.
Pulmonary adverse events that may be associated with alteplase during treatment of pulmonary embolism include pulmonary reembolization, pulmonary edema, and pleural effusion. Pulmonary edema has also been reported during the treatment of myocardial infarction. These events may be life-threatening and may lead to death.
Hypersensitivity, including urticarial/anaphylactic reactions, has been reported in association with alteplase. Angioedema has been observed during and up to 2 hours after alteplase infusion in patients treated for acute ischemic stroke and myocardial infarction. In many cases, patients received concomitant ACE inhibitors. Monitor patients treated with alteplase during and for several hours after the end of infusion. If signs of a hypersensitivity occur, discontinue alteplase and promptly institute appropriate therapy (e.g., antihistamines, IV corticosteroids, epinephrine).
Due to an increased risk for bleeding, alteplase is contraindicated in adult patients being treated for acute myocardial infarction or pulmonary embolism with the following concomitant conditions: aneurysm or arteriovenous malformation; known coagulopathy or bleeding diathesis; active internal bleeding; brain tumor; recent (within the last 3 months) intracranial or intraspinal surgery or serious head trauma; intracranial mass; or history of recent stroke. In adult patients being treated for ischemic stroke, alteplase is contraindicated in patients with the following concomitant conditions: intracranial or intraspinal surgery, or serious head trauma within the last 3 months; evidence of current intracranial bleeding or suspicion of subarachnoid hemorrhage on pretreatment evaluation; active internal bleeding; intracranial neoplasm, arteriovenous malformation, or aneurysm; bleeding diathesis including, but not limited to, current use of oral anticoagulants or an INR more than 1.7 or PT more than 15 seconds, administration of heparin within 48 hours preceding the onset of stroke and an elevated aPTT at presentation, or thrombocytopenia (platelet count less than 100,000/mm3). If serious bleeding occurs, discontinue the alteplase infusion and treat appropriately. Patients who present with seizures at onset of stroke, history of intracranial hemorrhage, or those who have had a recent or previous stroke are also at increased risk of bleeding when alteplase is used for acute ischemic stroke. Avoid use of thrombolytics in patients whom have recently (within the past 10 days) experienced trauma (including cardiopulmonary resuscitation). Pediatric patients with similar conditions receiving alteplase will also be at increased risk of bleeding. The manufacturer of alteplase recommends that, for the management of acute ischemic stroke in adults, treatment only be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage by a cranial computerized tomography (CT) scan or other diagnostic imaging method sensitive for the presence of hemorrhage. There is an increased risk of intracranial hemorrhage in patients with severe neurological deficit (e.g., NIHSS more than 22) at presentation. The risks of alteplase therapy may be increased in patients with major early infarct signs on CT (e.g., substantial edema, mass effect, or midline shift). The treatment of patients with minor neurological deficit or with rapidly improving symptoms is not recommended as the safety and efficacy in these patients has not been evaluated.
Alteplase is contraindicated in patients with severe uncontrolled hypertension. In adult patients with systolic blood pressure of 175 mmHg or more and/or diastolic blood pressure of 110 mmHg or more, the risks of bleeding with alteplase therapy are increased and should be weighed against the potential benefits. Although specific recommendations for blood pressure control in pediatric patients receiving alteplase are not available, monitor blood pressure frequently during and after alteplase administration. In trials in adults receiving alteplase for the management of acute ischemic stroke, blood pressure was actively controlled for 24 hours and monitored throughout the hospital stay. Guidelines for acute ischemic stroke exclude patients from alteplase use if systolic blood pressure is more than 185 mmHg or diastolic blood pressure is more than 110 mmHg. In patients with acute ischemic stroke with uncontrolled hypertension who are otherwise eligible for alteplase therapy, increase the frequency of blood pressure monitoring if systolic blood pressure is more than 180 mmHg or diastolic blood pressure is more than 105 mmHg. Administer antihypertensive medications to maintain blood pressure at or below these values. Ensure that the blood pressure is stabilized at a lower level before beginning treatment with alteplase, and maintain blood pressure below 180/105 mmHg for the first 24 hours after alteplase administration.
Avoid use of thrombolytics in patients whom have recently (within the past 10 days) undergone or experienced GI bleeding (e.g., peptic ulcer disease) or genitourinary bleeding, major surgery (e.g., coronary artery bypass graft surgery (CABG)), organ biopsy, or venipuncture of a noncompressible vessel. Avoid use of thrombolytics in patients with acute pericarditis, diabetic retinopathy (or other hemorrhagic ophthalmic conditions), or infectious endocarditis. Use thrombolytic therapy with extreme caution in other conditions that can be exacerbated as a result of bleeding or in which bleeding could be hazardous or difficult to control due to its location. Use alteplase for any indication with caution in patients who have recently received glycoprotein IIb/IIIa inhibitors or anticoagulant therapy (e.g., warfarin) due to the potential for enhanced risk of bleeding. The use of alteplase for occluded central venous catheters has not been studied in patients known to be at risk for bleeding events that may be associated with use of thrombolytics. Exercise caution in patients with active internal bleeding or other risk factors for bleeding within 48 hours of use.
Use systemic thrombolytics with caution in patients with hemostatic defects due to severe hepatic disease or renal failure or renal impairment or in any patient with significant hepatic dysfunction; the bleeding risk of alteplase may be increased and should be weighed against the anticipated benefits.
Avoid intramuscular injections and nonessential handling in patients receiving systemic thrombolytic therapy with alteplase. Systemic alteplase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Perform venipunctures carefully and only when necessary. If an arterial puncture is necessary, use an upper extremity vessel accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely for evidence of bleeding.
Use alteplase for the management of occluded catheters with caution in the presence of known or suspected infection in the catheter. Systemic infection can occur if thrombolytics are administered into an occluded IV or AV cannula that is proximal to an infection site or in the presence of septic thrombophlebitis, as the local infection can be released to the systemic circulation.
Alteplase may increase the risk of thromboembolic events in conditions where there is a high likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation. Alteplase has not been shown to adequately treat underlying deep vein thrombosis in patients with pulmonary embolism. Consider the potential risk of reembolization due to lysis of the underlying deep vein thrombi in patients with pulmonary embolism.
In exploratory, multivariate analyses, age more than 77 years was among baseline characteristics associated with an increased risk for intracranial hemorrhage. Efficacy results suggest a reduced but still favorable outcome in geriatric patients treated with alteplase for acute ischemic stroke. Although guidelines recommend expanded use of alteplase at 3 to 4.5 hours after stroke onset, patients older than 80 years are not eligible for alteplase use in the expanded time window. This age group was excluded from acute ischemic stroke clinical trials evaluating the expanded alteplase use window.
Data from published studies and case reports on alteplase use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Alteplase has been shown to have an embryocidal effect in rabbits when administered systemically in doses (3 mg/kg) approximately equal to the human exposure at the dose for acute myocardial infarction (AMI). No maternal or fetal toxicity was evident at doses (1 mg/kg) approximately 0.3 times the human exposure. In pregnant rats, no maternal or fetal toxicity was evident at doses (1 mg/kg) approximately 0.6 times the human dose for AMI dosed during the period of organogenesis. In pregnancy, labor, and obstetric delivery, the risks of bleeding with alteplase therapy are increased and should be weighed against the potential benefits.
There are no data on the presence of alteplase in human milk, the effects on the breast-feeding infant, or the effects on milk production. However, based on the drug's large molecular weight and short half-life, experts state that clinically significant amounts of drug are not expected to be found in breast milk.
For the treatment of acute myocardial infarction, STEMI, including abrupt coronary occlusion during percutaneous transluminal coronary angioplasty (PTCA)*, for reduction of cardiovascular mortality and heart failure:
-for the treatment of acute myocardial infarction, STEMI for reduction of cardiovascular mortality and heart failure:
Intravenous dosage (accelerated infusion):
Adults weighing more than 67 kg: 15 mg IV bolus, followed by 50 mg IV over next 30 minutes, and then 35 mg IV over the next 60 minutes. The safety and efficacy of the accelerated infusion have only been studied with concomitant heparin and aspirin. Fibrinolytic therapy is recommended for ST-elevation myocardial infarction (STEMI) patients with the onset of symptoms in the previous 12 hours when the anticipated first medical contact to primary PCI time is more than 120 minutes. Fibrinolytic therapy is reasonable for patients with STEMI if there is clinical and/or ECG evidence of ongoing ischemia within 12 to 24 hours of onset and a large area of myocardium at risk or hemodynamic instability. Additionally, fibrinolytic therapy is recommended for STEMI patients with cardiogenic shock who are not candidates for either PCI or CABG. When fibrinolytic therapy is chosen as primary reperfusion strategy, administer within 30 minutes of hospital arrival.
Adults weighing 67 kg or less: 15 mg IV bolus, followed by 0.75 mg/kg IV over next 30 minutes, and then 0.5 mg/kg IV over the next 60 minutes. The safety and efficacy of the accelerated infusion have only been studied with concomitant heparin and aspirin. Fibrinolytic therapy is recommended for ST-elevation myocardial infarction (STEMI) patients with the onset of symptoms in the previous 12 hours when the anticipated first medical contact to primary PCI time is more than 120 minutes. Fibrinolytic therapy is reasonable for patients with STEMI if there is clinical and/or ECG evidence of ongoing ischemia within 12 to 24 hours of onset and a large area of myocardium at risk or hemodynamic instability. Additionally, fibrinolytic therapy is recommended for STEMI patients with cardiogenic shock who are not candidates for either PCI or CABG. When fibrinolytic therapy is chosen as primary reperfusion strategy, administer within 30 minutes of hospital arrival.
Intravenous dosage (3-hour infusion):
Adults weighing 65 kg or more: 6 to 10 mg IV bolus, followed by 50 to 54 mg/hour IV for first hour, then 20 mg/hour IV for 2 hours.
Adults weighing less than 65 kg: 0.075 mg/kg mg IV bolus, followed by 0.675 mg/kg/hour IV for first hour, then 0.25 mg/kg/hour IV for 2 hours.
-for the treatment of abrupt coronary occlusion during percutaneous transluminal coronary angioplasty (PTCA)*:
Intracoronary dosage:
Adults: Dosage not established. 10 to 30 mg intracoronary over 5 to 20 minutes followed by IV infusion has been used.
Intravenous dosage:
Adults: Dosage not established. 40 to 50 mg IV over 1 hour after intracoronary dosing has been used.
For the treatment of acute pulmonary embolism:
Intravenous dosage (standard regimen):
Adults: 100 mg IV over 2 hours. Start parenteral anticoagulation near the end of or immediately after the alteplase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less.
Infants*, Children*, and Adolescents*: 0.5 mg/kg/hour IV for 6 hours is a commonly used regimen; doses of 0.01 to 3.75 mg/kg/hour for 1 to 192 hours have been reported. Heparin therapy either during or immediately following thrombolytic therapy has been recommended; the loading dose may be omitted. Increased bleeding complications have been reported in pediatric patients receiving higher doses; therefore, some authors recommend initiating therapy at the lower end of the dosage range and increasing the dose only if necessary for adequate lysis.
Neonates*: 0.1 to 0.3 mg/kg/hour IV for 6 to 48 hours has been recommended. Regimens reported in small case series and case reports of neonates (n = 94) have included loading doses up to 0.75 mg/kg IV over 10 to 60 minutes followed by infusions of 0.02 to 1 mg/kg/hour IV for 0.5 to 264 hours. Although the overall outcome in these reports was 94% patency restoration (68% to 79% complete clot dissolution and 14% to 26% partial clot dissolution), the number of patients in each report was too small and the regimens too varied to draw definitive conclusions regarding the appropriate dose. Heparin therapy either during or immediately following thrombolytic therapy has been recommended; the loading dose may be omitted. Increased bleeding complications have been reported in pediatric patients receiving higher doses; therefore, some authors recommend initiating therapy at the lower end of the dosage range and increasing the dose only if necessary for adequate lysis.
Intravenous dosage (accelerated regimen*):
Adults: 0.6 mg/kg (Max: 50 mg) IV over 15 minutes in persons with extreme hemodynamic instability, such as cardiac arrest.
For the treatment of acute ischemic stroke:
Intravenous dosage:
Adults: 0.9 mg/kg (Max: 90 mg) IV over 60 minutes with initial 10% of the total dose given as bolus over 1 minute within 3 hours, or 4.5 hours for select patients, of stroke symptom onset or baseline well state. Guidelines recommend alteplase treatment in the 3- to 4.5-hour window for patients 80 years or younger, without a history of diabetes or prior stroke, National Institutes of Health Stroke Scale (NIHSS) score of 25 or less, not taking any oral anticoagulants, and without imaging evidence of ischemic injury involving more than one-third of the middle cerebral artery territory.
Infants*, Children*, and Adolescents*: Guidelines do not recommend the use of thrombolytics for acute ischemic stroke in pediatric patients; however, 0.9 mg/kg (Max: 90 mg) IV over 60 minutes with initial 10% of the total dose given as bolus over 1 minute has been used in a small number of pediatric patients. Adult guideline recommendations were often not followed; poor neurologic outcome was common in the patients that received alteplase. In adults, alteplase is recommended to start within 3 hours, or 4.5 hours for select patients, of stroke symptom onset or baseline well state.
For the treatment of deep venous thrombosis (DVT)*:
Intrathrombus dosage:
Adults: 0.01 mg/kg/hour (Max: 1 mg/hour) catheter-directed continuous intrathrombus infusion. Guidelines recommend anticoagulant therapy alone over catheter-directed thrombolysis (CDT) in patients with acute proximal DVT; however, guidelines do state that patients who are most likely to benefit from CDT are those with iliofemoral DVT, symptoms for less than 14 days, good functional status, life expectancy of more than 1 year, and a low risk of bleeding. Use of pharmacomechanical CDT is suggested over the use of infusion-only CDT.
For the treatment of peripheral arterial thromboembolism*:
Intra-arterial dosage:
Adults: Various doses and administration times have been studied; the lowest effective dose has not been determined. Common doses used in combination with heparin include 0.5 to 2.5 mg/hour. Weight-based dosing of 0.05 to 0.1 mg/kg/hour for up to 12 hours (Max: 100 mg) also has been studied. In clinical trials, alteplase was administered by catheter-directed intra-arterial administration. Administration time varied but typically continued until complete lysis was achieved or for up to 12 hours. Guidelines recommend immediate systemic anticoagulation with unfractionated heparin in patients with acute limb ischemia due to arterial emboli or thrombosis and recommend reperfusion with surgery over intra-arterial thrombolysis.
For reestablishing patency of an occluded IV catheter:
Intracatheter Instillation dosage (Cathflo):
Adults: 2 mg/2 mL instilled into the dysfunctional catheter for 2 hours. A second dose may be instilled if catheter function is not restored 2 hours after the first dose. Efficacy and safety information for doses more than 2 mg/dose or total doses more than 4 mg is not available. Dwell times of 0.5 to 4 hours have been recommended. For multiple lumens, treat 1 lumen at a time. For subcutaneous ports, a dose of 2 mg diluted in 3 mL of 0.9% Sodium Chloride Injection has been recommended. Doses of 1 to 2 mg instilled into the lumen(s) of central venous catheters or PICC lines, allowed to dwell for 15 minutes to 4 hours, then removed by aspiration, have been reported effective in establishing patency.
Children and Adolescents weighing 30 kg or more: 2 mg/2 mL instilled into the dysfunctional catheter for 2 hours. A second dose may be instilled if catheter function is not restored 2 hours after the first dose. Efficacy and safety information for doses more than 2 mg/dose or total doses more than 4 mg is not available. Dwell times of 0.5 to 4 hours have been recommended. For multiple lumens, treat 1 lumen at a time. For subcutaneous ports, a dose of 2 mg diluted in 3 mL of 0.9% Sodium Chloride Injection has been recommended.
Children weighing 10 to 29 kg: 110% of the internal lumen volume of the catheter instilled with alteplase 1 mg/mL, not to exceed 2 mg/2 mL. A second dose may be instilled if catheter function is not restored 2 hours after the first dose. Efficacy and safety information for doses more than 2 mg/dose or total doses more than 4 mg is not available. Dwell times of 0.5 to 4 hours have been recommended. For multiple lumens, treat 1 lumen at a time. For subcutaneous ports, a dose of 2 mg diluted in 3 mL of 0.9% Sodium Chloride Injection has been recommended.
Neonates, Infants, and Children weighing less than 10 kg: 110% of the internal lumen volume of the catheter instilled with alteplase 1 mg/mL, not to exceed 2 mg/2 mL. A second dose may be instilled if catheter function is not restored 2 hours after the first dose. Efficacy and safety information for doses more than 2 mg/dose or total doses more than 4 mg is not available. A solution of 0.5 to 1 mg diluted in 2 mL of 0.9% Sodium Chloride Injection sufficient to fill the occluded catheter has also been used. Dwell times of 0.5 to 4 hours have been recommended. For multiple lumens, treat 1 lumen at a time. For subcutaneous ports, 0.5 mg diluted in 3 mL of 0.9% Sodium Chloride Injection has been recommended.
For intravascular catheter occlusion prophylaxis*:
Intracatheter instillation dosage (Cathflo)*:
Adults: 1 or 2 mg alteplase instilled in each catheter lumen at the end of hemodialysis session; 2 mg after each dialysis session and 1 mg alteplase in only 1 of 3 dialysis sessions each week, with heparin instilled after the other 2 sessions has been used.
For the management of pleural effusion* or pleural empyema*:
-for the treatment of pleural effusion*:
Intrapleural dosage*:
Infants, Children, and Adolescents: 4 mg intrapleurally as a single dose or as multiple doses 24 hours apart.
-for the treatment of pleural empyema*:
Intrapleural dosage*:
Adults: 10 mg intrapleurally twice daily for 3 days in combination with dornase alfa.
Infants, Children, and Adolescents: 2 to 4 mg intrapleurally every 8 to 24 hours for 3 days. Some studies have used in combination with dornase alfa.
INVESTIGATIONAL USE: For the treatment of acute respiratory distress syndrome (ARDS)* associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection*, the virus that causes coronavirus disease 2019 (COVID-19)*:
Intravenous dosage:
Adults: Available data are limited, and efficacy has not been established. Due to a lack of clinical data, the National Institutes of Health (NIH) COVID-19 treatment guidelines do not recommend for or against the use of thrombolytics, such as alteplase. 25 mg IV over 2 hours followed by 25 mg continuous IV infusion over 22 hours (Max: 0.9 mg/kg) has been used as salvage therapy. In a case series (n = 3) of critically ill patients with ARDS and respiratory failure given alteplase, an initial improvement in PaO2/FiO2 (P/F) ratio ranging from 11% to 100% was observed in all 3 patients; however, improvements were transient. Heparin was initiated or resumed immediately after the completion of alteplase infusion without bleeding complications. Redosing and/or using a higher bolus dose (50 to 100 mg) without holding anticoagulation is postulated that may provide a more durable response. Patients with a P/F ratio less than 50 and a pCO2 more than 60 despite prone positioning and maximal ventilatory support may be candidates for alteplase use, particularly if extracorporeal membrane oxygenation (ECMO) is not available. May also consider use in patients with progressive pulmonary deterioration where there is no further mechanical ventilation capacity. Additional clinical evaluation is needed.
For the treatment of frostbite*:
Intravenous or Intra-Arterial dosage:
Adults: 3 mg IV or intra-arterial bolus, then 10 mg/hour continuous IV or intra-arterial infusion starting within 24 to 48 hours of the initial cold injury and continuing until specialists recommend discontinuation. Administer anticoagulation concurrently. Guidelines suggest thrombolytic therapy to salvage at-risk tissue for deep frostbite injury with potential significant morbidity.
Maximum Dosage Limits:
-Adults
The maximum dosage is dependent on indication for therapy.
-Geriatric
The maximum dosage is dependent on indication for therapy.
-Adolescents
Safety and efficacy have not been established for systemic thrombolysis; various regimens have been used. For occluded catheters, instill no more than 4 mg/catheter.
-Children
Safety and efficacy have not been established for systemic thrombolysis; various regimens have been used. For occluded catheters, instill no more than 4 mg/catheter.
-Infants
Safety and efficacy have not been established for systemic thrombolysis; various regimens have been used. For occluded catheters, instill no more than 4 mg/catheter.
-Neonates
Safety and efficacy have not been established for systemic thrombolysis; various regimens have been used. For occluded catheters, instill no more than 4 mg/catheter.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. The risks of alteplase therapy may be increased in patients with significant hepatic impairment and should be weighed against the anticipated benefits.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abciximab: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Acetaminophen; Aspirin: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Acetaminophen; Ibuprofen: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Alpha interferons: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Aminocaproic Acid: (Contraindicated) The actions of aminocaproic acid can antagonize the actions of thrombolytic agents. Although antifibrinolytic agents can be beneficial in the treatment of thrombolytic-induced hemorrhage, the safety of concomitant administration of these agents has not been confirmed.
Aminolevulinic Acid: (Minor) Agents that decrease clotting, such as thrombolytic agents, could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Amlodipine; Celecoxib: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Anagrelide: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Antithrombin III: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
Apixaban: (Contraindicated) Due to the increased bleeding risk, avoid concurrent use of apixaban with thrombolytic agents.
Aprotinin: (Contraindicated) Aprotinin interferes with fibrinolysis by inhibiting the actions of kallikrein and plasmin, and it could inhibit fibrinolysis by thrombolytic agents. Although antifibrinolytic agents can be beneficial in the treatment of thrombolytic-induced hemorrhage, the safety of concomitant administration of these agents has not been confirmed.
Argatroban: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents with thrombin inhibitors.
Arsenic Trioxide: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Aspirin, ASA: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Aspirin, ASA; Caffeine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Aspirin, ASA; Dipyridamole: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Aspirin, ASA; Omeprazole: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Aspirin, ASA; Oxycodone: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and thrombolytic agents are used concomitantly. Coadministration of betrixaban and thrombolytic agents may increase the risk of bleeding.
Bexarotene: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Bismuth Subsalicylate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Bivalirudin: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents with thrombin inhibitors.
Bupivacaine; Meloxicam: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Celecoxib: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Celecoxib; Tramadol: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Chlorambucil: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Choline Salicylate; Magnesium Salicylate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Cilostazol: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Citalopram: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Clofarabine: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Clopidogrel: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Dabigatran: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
Dalteparin: (Moderate) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other agents known to increase the risk of bleeding such thrombolytic agents. Monitor clinical and laboratory response closely during concurrent use.
Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with thrombolytic agents.
Defibrotide: (Contraindicated) Coadministration of defibrotide with fibrinolytics (thrombolytic agents) is contraindicated. The pharmacodynamic activity and risk of hemorrhage with fibrinolytics are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic fibrinolytic therapy (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the fibrinolytic have abated.
Desvenlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Diclofenac: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Diclofenac; Misoprostol: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Diflunisal: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Diphenhydramine; Ibuprofen: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Diphenhydramine; Naproxen: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Dipyridamole: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Duloxetine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Edoxaban: (Major) Coadministration of edoxaban and thrombolytic agents should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
Enoxaparin: (Major) Whenever possible, discontinue agents which may enhance the risk of hemorrhage, including thrombolytic agents, before initiation of enoxaparin therapy. If coadministration is essential, conduct close clinical and laboratory monitoring.
Eptifibatide: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Escitalopram: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Estramustine: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Etodolac: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Fenoprofen: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents.
Fluoxetine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Flurbiprofen: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Fluvoxamine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Fondaparinux: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
Garlic, Allium sativum: (Moderate) Since garlic produces clinically-significant antiplatelet effects, it should be used cautiously in patients receiving thrombolytic agents. Avoid concurrent use of herbs which interact with thrombolytic agents when possible. If Garlic supplements are taken, monitor appropriate parameters to attain proper clinical endpoints.
Ginger, Zingiber officinale: (Moderate) Since ginger inhibits thromboxane synthetase, a platelet aggregation inducer, and is a prostacyclin agonist, use with caution during times when bleeding is a concern. This includes patients receiving thrombolytic agents, however, no clinical data are available.
Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and thrombolytic agents as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if coadministered with thrombolytic agents. Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea and thrombolytics are coadministered.
Heparin: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
Hydrocodone; Ibuprofen: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with coagulation such as thrombolytic agents; the risk of bleeding may be increased. If coadministration with thrombolytic agents is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
Ibuprofen: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Ibuprofen; Famotidine: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Ibuprofen; Oxycodone: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Ibuprofen; Pseudoephedrine: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Indomethacin: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Interferon Alfa-2b: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Interferon Alfa-n3: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Intravenous Lipid Emulsions: (Moderate) Fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents.
Ketoprofen: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Ketorolac: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Levomilnacipran: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SNRI.
Lomustine, CCNU: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Magnesium Salicylate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Meclofenamate Sodium: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Mefenamic Acid: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Meloxicam: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Methenamine; Sodium Salicylate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Methotrexate: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Methoxsalen: (Minor) Agents that decrease clotting, such as thrombolytic agents, could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs including increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking thrombolytic agents until data confirming the safety of this drug combination are available.
Milnacipran: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SNRI.
Nabumetone: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Naproxen: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Naproxen; Esomeprazole: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Naproxen; Pseudoephedrine: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Nitroglycerin: (Major) Two separate studies have shown that concomitant administration of IV nitroglycerin can compromise the therapeutic efficacy of alteplase. In one study, reperfusion occurred in 91% of patients receiving alteplase without nitroglycerin while only 44% of patients receiving alteplase with nitroglycerin were reperfused, however this was an uncontrolled study. In another controlled study, patients who did not receive concomitant IV nitroglycerin reperfused faster, more often, and had fewer reocclusions. It appears that when combined in vitro, nitroglycerin enhances the degradation of alteplase. Nitroglycerin may enhance the hepatic clearance of alteplase since alteplase plasma concentrations are lower in patients receiving concomitant nitroglycerin.
Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Olanzapine; Fluoxetine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Oxaprozin: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Paroxetine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Peginterferon Alfa-2a: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Peginterferon Alfa-2b: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Pemetrexed: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Pentosan: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
Photosensitizing agents (topical): (Minor) Agents that decrease clotting, such as thrombolytic agents, could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Piroxicam: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Platelet Inhibitors: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Pralatrexate: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytics.
Prasugrel: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Protein C Concentrate, Human: (Major) The concomitant use of protein C concentrate and alteplase, tPA may further increase the risk of bleeding from tPA. In clinical trials, several episodes of bleeding were reported. Concurrent anticoagulant medication may have been responsible for these bleeding episodes.
Prothrombin Complex Concentrate, Human: (Major) The concomitant use of protein C concentrate and alteplase, tPA may further increase the risk of bleeding from tPA. In clinical trials, several episodes of bleeding were reported. Concurrent anticoagulant medication may have been responsible for these bleeding episodes.
Rivaroxaban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with thrombolytic agents; the safety of concomitant use has not been studied.
Ropeginterferon alfa-2b: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Salicylates: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Salsalate: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Selective serotonin reuptake inhibitors: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Sertraline: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Sulindac: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Sumatriptan; Naproxen: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Thrombin Inhibitors: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents with thrombin inhibitors.
Ticagrelor: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Tirofiban: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Tolmetin: (Moderate) NSAIDs can cause GI bleeding, inhibit platelet aggregation, prolong bleeding time; these pharmacodynamic effects may be increased when administered to patients receiving thrombolytic agents. Patients receiving these drugs concurrently should be monitored closely for bleeding.
Tranexamic Acid: (Contraindicated) Antifibrinolytic agents, including tranexamic acid, can antagonize the actions of thrombolytic agents. Although antifibrinolytic agents can be beneficial in the treatment of thrombolytic-induced hemorrhage, the safety of concomitant administration of these agents has not been confirmed.
Trazodone: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with trazodone.
Tretinoin, ATRA: (Moderate) Patients with thrombocytopenia are at increased risk of bleeding complications. An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Venlafaxine: (Moderate) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered concurrently with venlafaxine.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with thrombolytic agents is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease clotting like thrombolytic agents could decrease the efficacy of verteporfin therapy.
Vilazodone: (Moderate) Platelet aggregation may be impaired by vilazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with vilazodone.
Vorapaxar: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Vorinostat: (Moderate) Due to the thrombocytopenic effects of vorinostat, an additive risk of bleeding may be seen in patients receiving concomitant thrombolytic agents.
Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with vortioxetine and instructed to promptly report any bleeding events to the practitioner.
Warfarin: (Contraindicated) Based on the pharmacology of warfarin, other thrombolytic agents could cause additive risk of bleeding when given concurrently with warfarin. Pre-treatment with oral anticoagulants is reported to be an independent risk factor for intracranial hemorrhage in thrombolytic-treated patients. Prothrombin times stabilized during administration of both agents will change slightly when heparin is discontinued.
Alteplase exerts its action on the endogenous fibrinolytic system to convert plasminogen to plasmin by directly hydrolyzing the arginine-valine bond in plasminogen. Plasmin degrades fibrin and fibrinogen as well as the procoagulant factors V and VIII. Unlike streptokinase or urokinase, most of the activity of alteplase is dependent on the presence of fibrin. Minimal amounts of plasminogen are converted to plasmin in the absence of fibrin. Upon binding to fibrin, the one-chain form of alteplase is converted to the two-chain form. Both forms have similar fibrinolytic and plasminogen-activating potential; however, the one-chain alteplase is considerably less active in the absence of fibrin. Alteplase that is bound to fibrin acquires a high affinity for plasminogen, which is responsible for an increased activity at the fibrin surface compared to the circulation.
Alteplase is administered by IV infusion. The distribution of this agent has not been described; the initial volume of distribution approximates plasma volume. It is unknown whether alteplase crosses the placenta or is excreted into breast milk. Hepatic clearance is the predominant route of metabolism. More than 50% of the drug is cleared following discontinuation of IV infusion and 80% is cleared within 10 minutes. Limited studies in patients with myocardial infarction and patients with thromboembolic disease indicate that the terminal half-life of alteplase is approximately 45 and 30 minutes, respectively. Alteplase has been shown to be primarily excreted in the urine (80%).
-Special Populations
Hepatic Impairment
There is some evidence to suggest a longer elimination half-life of alteplase in patients with hepatic impairment; use with caution in patients with significant hepatic disease.
Other
Patients with Myocardial Infarction
Plasma concentrations of alteplase are related to dose and rate of administration. Patients with myocardial infarction (MI) show greater variation of pharmacokinetic properties than do healthy individuals. In MI patients, an infusion of alteplase at a rate of 4 to 8.3 mcg/kg/minute resulted in steady-state plasma concentrations of 0.52 to 1.4 mcg/mL; there was large variability among patients receiving infusions at the same rate. In MI patients receiving accelerated infusion of alteplase (i.e., 15 mg alteplase as an IV bolus, then 50 mg IV over 30 minutes, then 35 mg over 60 minutes), the mean steady-state plasma concentrations of alteplase were 3.2 mcg/mL; however, the half-life was similar to that reported with conventional administration.