ACTIVASE

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
-50 mg vials: Vials contain a vacuum; do not use if vacuum is not present. Use a large bore needle (e.g., 18 gauge) and a syringe to add the supplied Sterile Water for Injection to the alteplase vial to make a 1 mg/mL solution. Direct the stream of water into the lyophilized cake. Slight foaming upon reconstitution may occur; standing undisturbed for several minutes is sufficient to allow dissipation of any large bubbles. The reconstituted product is a colorless to pale yellow transparent solution.
-100 mg vials: Vials do not contain vacuum. Keeping the vial of Sterile Water for Injection upright, insert the piercing pin of the provided transfer device vertically into the center of the stopper. Push the alteplase vial down on the transfer device so that the piercing pin is inserted through the center of the vial stopper. Invert the 2 vials so that the alteplase vial is on the bottom and allow the entire amount of water to flow into the vial (about 0.5 mL will remain in the Sterile Water for Injection vial). This will take about 2 minutes. The concentration of alteplase solution is 1 mg/mL. Separate the alteplase vial from the transfer device and gently swirl to dissolve the powder. DO NOT SHAKE.

Dilution
-Administer the 1 mg/mL reconstituted solution. Alternatively, further dilute the solution with 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. After dilution, the solution is stable for up to 8 hours at room temperature.
-Although not recommended for routine clinical use, further dilution to a minimum concentration of 0.2 mg/mL with 0.9% Sodium Chloride Injection can be done; precipitate formation has been associated with concentrations less than 0.2 mg/mL.
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 1 mg/mL.


Preparation of bolus dose
-Prepare the bolus in 1 of 3 ways:-Remove the appropriate indication-specific volume from the reconstituted vial using a syringe and needle. If this method is used with 50 mg vials, do not prime the syringe with air and insert the needle into the vial stopper. If the 100 mg vial is used, insert the needle 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 (1 mg/mL) at the initiation of the infusion.


Intermittent IV Infusion
-For the 50-mg vial: Administer using a polyvinyl chloride bag or glass vial and infusion set.
-For the 100-mg vial: 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 of alteplase from the plastic molded capping attached to the bottom of the vial.
-Length of infusion depends upon indication.

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. Major and minor bleeding events associated with alteplase treatment have been reported in 17% and 26% of pediatric patients, respectively. Rates of internal bleeding reported in adult patients include 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 reported in adult patients includes ecchymosis (1%), gingival bleeding (less than 1%), and epistaxis (less than 1%). In clinical studies of adult patients with acute ischemic stroke (n = 624), a higher incidence of intracranial bleeding, especially symptomatic intracranial bleeding, was seen in patients receiving alteplase compared to placebo (total intracranial bleeding: 15.4% vs. 6.4%; symptomatic intracranial bleeding: 8% vs. 1.3%). However, there was no increase in the incidence of 90-day mortality or severe disability in patients receiving alteplase. Studies in adults indicate that the incidence of intracranial bleeding is dose-related, with the greatest percentage occurring at a dosage of 150 mg (1.3%) compared to 100 mg (0.4%). A study of another alteplase product, Actilyse, suggested that doses greater 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 patients as compared to 3.8% of placebo patients in clinical trials (p = 0.19). Bleeding occurs most commonly at access sites such as catheter insertion sites or venipuncture sites. Patients with preexisting coagulopathies are at the highest risk for developing bleeding complications. During clinical trials with alteplase for catheter occlusion, 3 patients had a major GI bleed 2 to 3 days after alteplase treatment. One 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 of alteplase to these events cannot be ruled out. There have been no reports of intracranial hemorrhage with alteplase use for occluded catheters. Hemorrhage could result from concomitant therapy with heparin or other platelet aggregation inhibitors. If serious or severe bleeding occurs during therapy, discontinue alteplase immediately and treat appropriately. 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 in adult patients.

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.

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.

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).

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.

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.

Description: Alteplase is a thrombolytic agent used systemically for thrombolysis and locally for restoring patency to occluded IV catheters. Alteplase is a recombinant form of human tissue plasminogen activator and is produced from genetically modified Chinese hamster ovary cells. Although alteplase is considerably more expensive than streptokinase, alteplase is not associated with antigenicity. For this reason, as well as in vitro evidence of improved clot lysis and fibrin specificity compared to streptokinase and urokinase, alteplase is considered the thrombolytic of choice in pediatric patients. Alteplase for the restoration of catheter patency (Cathflo Activase) is FDA-approved in pediatric patients as young as neonates; although not FDA-approved for systemic thrombolysis, alteplase (Activase) has been used off-label in patients as young as neonates.

General Dosing Information for systemic thrombolysis with alteplase
-The American College of Chest Physicians (ACCP) recommends thrombolytic therapy for bilateral renal vein thrombosis only when there is evidence of renal impairment and for venous thromboembolism or femoral artery thrombosis only when there is major vessel occlusion compromising organs or limbs.
-Plasminogen replacement via administration of fresh frozen plasma is recommended prior to thrombolytic therapy in neonates and older pediatric patients with physiological or pathological plasminogen deficiency.
-A fibrinogen concentration more than 1 g/L and a platelet count more than 100 x 109/L are recommended in pediatric patients during alteplase therapy.

For the treatment of acute pulmonary embolism*, peripheral arterial thromboembolism*, deep venous thrombosis (DVT)*, renal vein thrombosis*, and acute myocardial infarction* due to coronary artery thrombosis*:
Continuous Intravenous Infusion dosage:
Neonates: 0.1 to 0.3 mg/kg/hour continuous IV infusion for 6 to 48 hours. Regimens reported in small case series and case reports of neonates (n = 94) have included loading doses of 0 to 0.75 mg/kg IV over 10 to 60 minutes followed by 0.02 to 1 mg/kg/hour continuous IV infusion 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.
Infants, Children, and Adolescents: 0.5 mg/kg/hour continuous IV infusion for 6 hours is a commonly used regimen; regimens of 0.01 to 3.75 mg/kg/hour continuous IV infusion 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.

For the treatment of acute ischemic stroke*:
Intravenous dosage:
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 reestablishing patency of an occluded IV catheter:
Intracatheter Instillation dosage (Cathflo):
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.
Infants and 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.
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.

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*:
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.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established for systemic thrombolysis; various regimens have been used off-label. 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.
-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.
-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.

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; weigh potential risks 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

Monograph content under development

Mechanism of Action: 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.

Pharmacokinetics: Alteplase is administered by IV infusion. The distribution of this agent has not been described; the initial volume of distribution approximates plasma volume. Hepatic metabolism is the predominant route of clearance. The initial plasma half-life of alteplase in adult patients is less than 5 minutes. The terminal half-life in adults ranges from 15 to 88 minutes. Within 10 minutes of discontinuation of IV infusion, 80% of unbound alteplase is cleared.

Affected cytochrome P450 isoenzymes: none