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Activase Rt-PA (Acute Ischemic Stroke) (Alteplase)
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Pharmacology
Stroke: Acute Ischemic Stroke: Alteplase is a serine protease which has the property of fibrin-enhanced conversion of plasminogen to plasmin. Alteplase produces minimal conversion of plasminogen in the absence of fibrin; and when introduced into the systemic circulation, alteplase binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin. This initiates local fibrinolysis with minimal systemic effects. Following administration of alteplase, there is a decrease (20to 30%) in circulating fibrinogen. Decreases in plasminogen and a 2-antiplasmin are also evident.
Alteplase is cleared rapidly from circulating plasma with an initial half-life of less than 5minutes. The plasma clearance of alteplase is approximately 500mL/min. The clearance is mediated primarily by the liver.
Stroke: Acute Ischemic Stroke: Alteplase is a serine protease which has the property of fibrin-enhanced conversion of plasminogen to plasmin. Alteplase produces minimal conversion of plasminogen in the absence of fibrin; and when introduced into the systemic circulation, alteplase binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin. This initiates local fibrinolysis with minimal systemic effects. Following administration of alteplase, there is a decrease (20to 30%) in circulating fibrinogen. Decreases in plasminogen and a 2-antiplasmin are also evident.
Alteplase is cleared rapidly from circulating plasma with an initial half-life of less than 5minutes. The plasma clearance of alteplase is approximately 500mL/min. The clearance is mediated primarily by the liver.
Indications
Stroke: Acute Ischemic Stroke: Alteplase Is A Serine Protease Which Has The Property Of Fibrin-enhanced Conversion Of Plasminogen To Plasmin. Alteplase Produces Minimal Conversion Of Plasminogen In The Absence Of Fibrin; And When Introduced Into The Systemic Circulation, Alteplase Binds To Fibrin In A Thrombus And Converts The Entrapped Plasminogen To Plasmin. This Initiates Local Fibrinolysis With Minimal Systemic Effects. Following Administration Of Alteplase, There Is A Decrease (20to 30%) In Circulating Fibrinogen. Decreases In Plasminogen And A 2-antiplasmin Are Also Evident.
Alteplase Is Cleared Rapidly From Circulating Plasma With An Initial Half-life Of Less Than 5minutes. The Plasma Clearance Of Alteplase Is Approximately 500mL/min. The Clearance Is Mediated Primarily By The Liver.
Stroke: Acute Ischemic Stroke: Alteplase Is A Serine Protease Which Has The Property Of Fibrin-enhanced Conversion Of Plasminogen To Plasmin. Alteplase Produces Minimal Conversion Of Plasminogen In The Absence Of Fibrin; And When Introduced Into The Systemic Circulation, Alteplase Binds To Fibrin In A Thrombus And Converts The Entrapped Plasminogen To Plasmin. This Initiates Local Fibrinolysis With Minimal Systemic Effects. Following Administration Of Alteplase, There Is A Decrease (20to 30%) In Circulating Fibrinogen. Decreases In Plasminogen And A 2-antiplasmin Are Also Evident.
Alteplase Is Cleared Rapidly From Circulating Plasma With An Initial Half-life Of Less Than 5minutes. The Plasma Clearance Of Alteplase Is Approximately 500mL/min. The Clearance Is Mediated Primarily By The Liver.
Contraindications
Stroke: Acute Ischemic Stroke: In the following situations because of an increased risk of bleeding, which could result in significant disability or death: symptom onset greater than 3hours; evidence of intracranial hemorrhage on pretreatment evaluation; suspicion of subarachnoid hemorrhage; recent intracranial surgery or serious head trauma or recent previous stroke; history of intracranial hemorrhage; uncontrolled hypertension at time of treatment (e.g., >185mmHg systolic or >110mmHg diastolic); seizure at the onset of stroke; active internal bleeding; intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diathesis including but not limited to: current use of oral anticoagulants (e.g., warfarin sodium) with prothrombin time (PT) >15seconds, administration of heparin within 48hours preceding the onset of stroke and an elevated activated partial thromboplastin time (aPTT) at presentation, and platelet count <100000/mm 3.
Stroke: Acute Ischemic Stroke: In the following situations because of an increased risk of bleeding, which could result in significant disability or death: symptom onset greater than 3hours; evidence of intracranial hemorrhage on pretreatment evaluation; suspicion of subarachnoid hemorrhage; recent intracranial surgery or serious head trauma or recent previous stroke; history of intracranial hemorrhage; uncontrolled hypertension at time of treatment (e.g., >185mmHg systolic or >110mmHg diastolic); seizure at the onset of stroke; active internal bleeding; intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diathesis including but not limited to: current use of oral anticoagulants (e.g., warfarin sodium) with prothrombin time (PT) >15seconds, administration of heparin within 48hours preceding the onset of stroke and an elevated activated partial thromboplastin time (aPTT) at presentation, and platelet count <100000/mm 3.
Safety Information / Warning
Fibrin will be lysed during the infusion of alteplase and bleeding from recent puncture sites may occur. Therefore, therapy with alteplase, as with other thrombolytic agents, requires careful attention to all potential bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites and needle puncture sites).
I.M. injections and nonessential handling of the patient should be avoided during and immediately following treatment with alteplase. Venipunctures should be performed carefully and only as required.
Should an arterial puncture be necessary during an infusion of alteplase, it is preferable to use an upper extremity vessel that is accessible to manual compression. Pressure should be applied for at least 30minutes, a pressure dressing applied and the puncture site checked frequently for evidence of bleeding.
Should serious bleeding in a critical location (not controllable by local pressure) occur, the infusion of alteplase and any other concomitant anticoagulant should be discontinued immediately and treatment initiated (See Overdose: Symptoms and Treatment).
In the following conditions, the risks of alteplase therapy may be increased and should be weighed against the anticipated benefits: recent (within 10days) major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels; clinical evidence or history of transient ischemic attacks; recent gastrointestinal or genitourinary bleeding (within 10days); recent trauma (within 10days); a history or clinical evidence of hypertensive disease in a patient over 70years old; advanced age, e.g., over 75years old; high likelihood or known presence of left heart thrombus, e.g., mitral stenosis with atrial fibrillation; apical MI, with thrombus; acute pericarditis; subacute bacterial endocarditis; hemostatic defects including those secondary to severe hepatic or renal disease; significant liver dysfunction, e.g., prolonged prothrombin time; pregnancy; diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site; patients currently receiving oral anticoagulants, e.g., warfarin sodium; any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.
Cholesterol Embolization: Cholesterol embolization has been reported rarely in patients treated with all types of thrombolytic agents; the true incidence is unknown. This serious condition, which can be lethal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. Clinical features of cholesterol embolism include livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.
Stroke: Acute Ischemic Stroke: Alteplase is a drug known to cause severe bleeding and an increased incidence of intracranial hemorrhage. Use of alteplase for the treatment of stroke is limited to physicians experienced in acute stroke management, who are treating patients in a hospital setting equipped with appropriate laboratory facilities to follow the neurological (CT scan) and hematological status of the patient.
Two European studies have been conducted by the European Collaborative Acute Stroke Study Group, referred to as ECASS I and ECASS II, using another alteplase product, Actilyse.
The ECASS I study suggested that doses greater than 0.9mg/kg may be associated with increased risk of ICH. The dose of 0.9mg/kg (maximum 90mg) should not be exceeded in the management of acute ischemic stroke.
The results of the ECASS II study indicated a trend towards efficacy when the treatment was initiated within 6 hours or less after the onset of the event, although the results do not confirm a statistical benefit for alteplase. It was concluded that despite the increased risk for ICH, thrombolysis with alteplase may lead to a clinically relevant improvement in outcome in selected patients and in experienced centres.
Based on burden of evidence, treatment of patients with acute ischemic stroke more than 3hours after symptom onset is not recommended (see Contraindications). The risks of alteplase therapy to treat acute ischemic stroke may be increased in the following conditions and should be weighed against the anticipated benefits: Patients with severe neurological deficit (e.g., NIHSS >22) at presentation. There is an increased risk of intracranial hemorrhage in these patients. Patients with major early infarct signs on a computerized cranial tomography (CT) scan (e.g., substantial edema, mass effect, or midline shift).
In patients without recent use of oral anticoagulants or heparin, alteplase treatment can be initiated prior to the availability of coagulation study results. However, infusion should be discontinued if either a pretreatment prothrombin time (PT) >15seconds or an elevated activated partial thromboplastin time (aPTT) is identified.
Treatment must be limited to facilities that can provide appropriate evaluation and management of ICH.
The safety and efficacy of treatment with alteplase in patients with minor neurological deficit or with rapidly improving symptoms prior to the start of alteplase administration has not been evaluated.
Antithrombotics: The concomitant use of heparin or ASA during the first 24hours following symptom onset were prohibited in The NINDS t-PA Stroke Trial. The safety of such concomitant use with alteplase for the management of acute ischemic stroke is unknown.
Fibrin will be lysed during the infusion of alteplase and bleeding from recent puncture sites may occur. Therefore, therapy with alteplase, as with other thrombolytic agents, requires careful attention to all potential bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites and needle puncture sites).
I.M. injections and nonessential handling of the patient should be avoided during and immediately following treatment with alteplase. Venipunctures should be performed carefully and only as required.
Should an arterial puncture be necessary during an infusion of alteplase, it is preferable to use an upper extremity vessel that is accessible to manual compression. Pressure should be applied for at least 30minutes, a pressure dressing applied and the puncture site checked frequently for evidence of bleeding.
Should serious bleeding in a critical location (not controllable by local pressure) occur, the infusion of alteplase and any other concomitant anticoagulant should be discontinued immediately and treatment initiated (See Overdose: Symptoms and Treatment).
In the following conditions, the risks of alteplase therapy may be increased and should be weighed against the anticipated benefits: recent (within 10days) major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels; clinical evidence or history of transient ischemic attacks; recent gastrointestinal or genitourinary bleeding (within 10days); recent trauma (within 10days); a history or clinical evidence of hypertensive disease in a patient over 70years old; advanced age, e.g., over 75years old; high likelihood or known presence of left heart thrombus, e.g., mitral stenosis with atrial fibrillation; apical MI, with thrombus; acute pericarditis; subacute bacterial endocarditis; hemostatic defects including those secondary to severe hepatic or renal disease; significant liver dysfunction, e.g., prolonged prothrombin time; pregnancy; diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site; patients currently receiving oral anticoagulants, e.g., warfarin sodium; any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location.
Cholesterol Embolization: Cholesterol embolization has been reported rarely in patients treated with all types of thrombolytic agents; the true incidence is unknown. This serious condition, which can be lethal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy. Clinical features of cholesterol embolism include livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction, and rhabdomyolysis.
Precautions
Stroke: Acute Ischemic Stroke: Alteplase must be administered in a hospital setting where the appropriate diagnostic and monitoring techniques are readily available.
Noncompressible arterial puncture must be avoided. Arterial and venous punctures should be minimized. In the event of serious bleeding, alteplase and heparin should be discontinued immediately. Heparin effects can be reversed by protamine.
Drug Interactions : The interaction of alteplase with other drugs has not been studied. In addition to bleeding associated with heparin and warfarin, drugs that alter platelet function (such as ASA) may increase the risk of bleeding if administered prior to, during or after alteplase infusion.
Laboratory Tests: During alteplase infusion, coagulation tests and/or measures of fibrinolytic activity may be performed if desired. However, routine measurements of fibrinogen as well as fibrinogen degradation products are unreliable, and should not be undertaken unless specific precautions are taken to prevent in vitro artifacts. Alteplase is a serine protease that when present in blood in pharmacologic concentrations remains active under in vitro conditions. This can lead to degradation of fibrinogen in a blood sample removed for analysis. Collection of blood samples on aprotinin (150to 200units/mL) can to some extent mitigate this phenomenon.
Geriatrics: The risks of therapy may be increased in the elderly (see Warnings).
In alteplase-treated patients (NINDS study) of advanced age (e.g., >77years of age), the trend toward increased risk for symptomatic ICH within the first 36hours was more prominent. Similar trends were also seen for total ICH and for all-cause 90-day mortality. Analyses for efficacy suggested a reduced but still favorable clinical outcome for these patients.
Children: Safety and effectiveness of alteplase in children has not been established. Therefore treatment of such patients is not recommended.
Pregnancy: Reproduction studies have not been conducted with alteplase. It is also not known whether alteplase can cause fetal harm when administered to a pregnant woman. Alteplase should be given to a pregnant woman only if clearly needed.
Lactation: It is not known whether alteplase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alteplase is administered to a nursing woman.
Readministration: There has been little documentation of readministration of alteplase. Readministration should be undertaken with caution. Less than 0.5% of patients receiving single courses of alteplase therapy have experienced transient antibody formation. Nevertheless, if an anaphylactoid reaction occurs, the infusion should be discontinued immediately and appropriate therapy initiated.
Stroke: Acute Ischemic Stroke: Alteplase must be administered in a hospital setting where the appropriate diagnostic and monitoring techniques are readily available.
Noncompressible arterial puncture must be avoided. Arterial and venous punctures should be minimized. In the event of serious bleeding, alteplase and heparin should be discontinued immediately. Heparin effects can be reversed by protamine.
Drug Interactions : The interaction of alteplase with other drugs has not been studied. In addition to bleeding associated with heparin and warfarin, drugs that alter platelet function (such as ASA) may increase the risk of bleeding if administered prior to, during or after alteplase infusion.
Laboratory Tests: During alteplase infusion, coagulation tests and/or measures of fibrinolytic activity may be performed if desired. However, routine measurements of fibrinogen as well as fibrinogen degradation products are unreliable, and should not be undertaken unless specific precautions are taken to prevent in vitro artifacts. Alteplase is a serine protease that when present in blood in pharmacologic concentrations remains active under in vitro conditions. This can lead to degradation of fibrinogen in a blood sample removed for analysis. Collection of blood samples on aprotinin (150to 200units/mL) can to some extent mitigate this phenomenon.
Geriatrics: The risks of therapy may be increased in the elderly (see Warnings).
In alteplase-treated patients (NINDS study) of advanced age (e.g., >77years of age), the trend toward increased risk for symptomatic ICH within the first 36hours was more prominent. Similar trends were also seen for total ICH and for all-cause 90-day mortality. Analyses for efficacy suggested a reduced but still favorable clinical outcome for these patients.
Children: Safety and effectiveness of alteplase in children has not been established. Therefore treatment of such patients is not recommended.
Pregnancy: Reproduction studies have not been conducted with alteplase. It is also not known whether alteplase can cause fetal harm when administered to a pregnant woman. Alteplase should be given to a pregnant woman only if clearly needed.
Lactation: It is not known whether alteplase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alteplase is administered to a nursing woman.
Readministration: There has been little documentation of readministration of alteplase. Readministration should be undertaken with caution. Less than 0.5% of patients receiving single courses of alteplase therapy have experienced transient antibody formation. Nevertheless, if an anaphylactoid reaction occurs, the infusion should be discontinued immediately and appropriate therapy initiated.
Side Effects / Adverse Effects
Bleeding events other than ICH were noted in the studies of acute ischemic stroke and were consistent with the general safety profile of alteplase. In the NINDS t-PA Stroke Trial (Parts 1 and 2), the frequency of bleeding requiring red blood cell transfusions was 6.4% for alteplase-treated patients compared to 3.8% for placebo (p=0.19, using Mantel-Haenszel Chi-Square).
Allergic Reactions: Allergic-type reactions, e.g., anaphylactoid reaction, laryngeal edema, rash and urticaria have been reported very rarely (<0.02%). A cause and effect relationship to alteplase therapy has not been established.
Stroke: Acute Ischemic Stroke: The incidence of ICH, especially symptomatic ICH, in patients with acute ischemic stroke was higher in alteplase-treated patients than placebo patients.
The incidences of ICH, and new ischemic stroke following alteplase treatment compared to placebo are presented in TableII as a combined safety analysis (n=624) for Parts1 and2. These data indicated a significant increase in ICH following alteplase treatment, particularly symptomatic ICH within 36hours. Symptomatic ICH within 36hours was experienced by 2of 312 (0.6%) of placebo-treated patients and 20 of 312 (6.4%) alteplase-treated patients (p<0.01). Potential predictors of symptomatic ICH within 36hours of study drug administration were baseline values of NIHSS score, fibrinogen (<200mg/dL), and platelet count (<150000/uL). These predictors were the same in both treatment groups.
Bleeding events other than ICH were noted in the studies of acute ischemic stroke and were consistent with the general safety profile of alteplase. In the NINDS t-PA Stroke Trial (Parts 1 and 2), the frequency of bleeding requiring red blood cell transfusions was 6.4% for alteplase-treated patients compared to 3.8% for placebo (p=0.19, using Mantel-Haenszel Chi-Square).
Allergic Reactions: Allergic-type reactions, e.g., anaphylactoid reaction, laryngeal edema, rash and urticaria have been reported very rarely (<0.02%). A cause and effect relationship to alteplase therapy has not been established.
Overdose
Symptoms and Treatment: Stroke: Acute Ischemic Stroke: Overdosage could lead to serious bleeding. Should serious bleeding occur in a critical location, the infusion of alteplase and any other concomitant anticoagulant should be discontinued immediately. If necessary, blood loss and reversal of the bleeding tendency can be managed with whole blood or packed red cells. In the event of clinically significant fibrinogen depletion, fresh frozen plasma or cryoprecipitate can be infused.
Symptoms and Treatment: Stroke: Acute Ischemic Stroke: Overdosage could lead to serious bleeding. Should serious bleeding occur in a critical location, the infusion of alteplase and any other concomitant anticoagulant should be discontinued immediately. If necessary, blood loss and reversal of the bleeding tendency can be managed with whole blood or packed red cells. In the event of clinically significant fibrinogen depletion, fresh frozen plasma or cryoprecipitate can be infused.
Recommended Dosage
Stroke: Acute Ischemic Stroke: Alteplase is intended for i.v. use only. It should be given via a dedicated i.v. line with an infusion pump. Extravasation of alteplase infusion can cause ecchymosis and/or inflammation. Management consists of terminating the infusion at the i.v. site and application of local therapy.
The recommended dose is 0.9 mg/kg (maximum of 90mg) infused over 60 minutes with 10% of the total dose administered as an initial i.v. bolus over 1minute.
The safety and efficacy of this regimen with concomitant administration of heparin and ASA during the first 24hours after symptom onset has not been investigated.
The dose for treatment of acute ischemic stroke should not exceed 90mg.
A. The bolus dose may be prepared in one of the following ways: 1.By removing the appropriate volume from the vial of reconstituted (1mg/mL) alteplase using a syringe and needle. If this method is used with the 50mg vials, the syringe should not be primed with air and the needle should be inserted into the alteplase-vial stopper. If the 100mg vial is used, the needle should be inserted away from the puncture mark made by the transfer device. 2.By removing the appropriate volume from a port (second injection site) on the infusion line after the infusion set is primed. 3.By programming an infusion pump to deliver the appropriate volume as a bolus at the initiation of the infusion. B.The remainder of the alteplase dose may be administered as follows: 50mg Vials: Administer using either a polyvinyl chloride bag or glass vial and infusion set. 100mg Vials: Remove from the vial any quantity of drug in excess of that specified for patient treatment. 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 alteplase vial from the plastic molded capping attached to the bottom of the vial.
Reconstitution and Dilution: Alteplase should be reconstituted by aseptically adding to the vial, the appropriate volume of Sterile Water for Injection, USP [SWFI] (50mL for 50mg vials, 100mL for 100mg vials). It is important that alteplase be reconstituted only with Sterile Water for Injection, USP, without preservatives. Do not use Bacteriostatic Water for Injection. The reconstituted preparation results in a colorless to pale yellow transparent solution containing alteplase 1.0mg/mL at a pH of 7.3. The osmolality of this solution is approximately 215mOsm/kg.
Before further dilution or administration, parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. Because alteplase contains no preservatives, it should be reconstituted immediately before use (see Stability and Storage).
The reconstituted solution may be diluted further immediately before administration to yield concentrations as low as 0.5mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Excessive agitation during dilution should be avoided; mixing should be accomplished with gentle swirling and/or slow inversion. Do not use other infusion solutions e.g., Sterile Water for Injection, USP, or preservative containing solutions for further dilution.
No other medication should be added to alteplase solution. Solutions should be administered as described above. Unused infusion solution should be immediately discarded.
50 mg Vials: Using a large bore needle (e.g., 18gauge), and the accompanying 50mL Sterile Water for Injection, USP, direct the stream of Sterile Water for Injection, USP into the lyophilized cake. Do not use if vacuum is not present. Slight foaming upon reconstitution is not unusual; standing undisturbed for several minutes is usually sufficient to allow dissipation of any large bubbles. Excessive or vigorous shaking should be avoided.
100 mg Vials: Using the transfer device provided, the contents of the accompanying 100mL vial of Sterile Water for Injection, USP should be added to the contents of the 100mg vial of alteplase powder. Slight foaming upon reconstitution is not unusual; standing undisturbed for several minutes is usually sufficient to allow dissipation of any large bubbles. No vacuum is present in 100mg vials. Please refer to the accompanying instructions for Reconstitution and Administration of the 100mg vials: 1.Use aseptic technique throughout.
2.Remove the protective flip-caps from 1vial of alteplase and 1vial of Sterile Water for Injection, USP [SWFI].
3.Open the package containing the transfer device by peeling the paper label off the package.
4.Remove the protective cap from one end of the transfer device and keeping the vial of SWFI upright, insert the piercing pin vertically into the centre of the stopper of the vial of SWFI.
5.Remove the protective cap from the other end of the transfer device. Do not invert the vial of SWFI.
6.Holding the vial of alteplase upside-down, position it so that the centre of the stopper is directly over the exposed piercing pin of the transfer device.
7.Push the vial of alteplase down so that the piercing pin is inserted through the centre of the alteplase stopper.
8.Invert the 2vials so that the vial of alteplase is on the bottom (upright) and the vial of SWFI is upside-down, allowing the SWFI to flow down through the transfer device. Allow the entire contents of the vial of SWFI to flow into the alteplase vial (approximately 0.5mL of SWFI will remain in the diluent vial). Approximately 2minutes are required for this procedure.
9.Remove the transfer device and the empty SWFI vial from the alteplase vial. Safely discard both the transfer device and the empty diluent vial according to institutional procedures.
10.Swirl gently to dissolve the alteplase powder. Do not shake.
Stability and Storage: Lyophilized alteplase is stable up to the expiration date stamped on the vial when stored at controlled temperatures between 2and 30°C. Protect the lyophilized material during extended storage from excessive exposure to light.
Unused reconstituted alteplase (in the vial) may be stored at 2to 30°C for up to 8hours. After that time, any unused portion of the reconstituted material should be discarded. During the period of reconstitution and infusion, protection from light is not necessary.
Stroke: Acute Ischemic Stroke: Alteplase is intended for i.v. use only. It should be given via a dedicated i.v. line with an infusion pump. Extravasation of alteplase infusion can cause ecchymosis and/or inflammation. Management consists of terminating the infusion at the i.v. site and application of local therapy.
The recommended dose is 0.9 mg/kg (maximum of 90mg) infused over 60 minutes with 10% of the total dose administered as an initial i.v. bolus over 1minute.
The safety and efficacy of this regimen with concomitant administration of heparin and ASA during the first 24hours after symptom onset has not been investigated.
The dose for treatment of acute ischemic stroke should not exceed 90mg.
A. The bolus dose may be prepared in one of the following ways: 1.By removing the appropriate volume from the vial of reconstituted (1mg/mL) alteplase using a syringe and needle. If this method is used with the 50mg vials, the syringe should not be primed with air and the needle should be inserted into the alteplase-vial stopper. If the 100mg vial is used, the needle should be inserted away from the puncture mark made by the transfer device. 2.By removing the appropriate volume from a port (second injection site) on the infusion line after the infusion set is primed. 3.By programming an infusion pump to deliver the appropriate volume as a bolus at the initiation of the infusion. B.The remainder of the alteplase dose may be administered as follows: 50mg Vials: Administer using either a polyvinyl chloride bag or glass vial and infusion set. 100mg Vials: Remove from the vial any quantity of drug in excess of that specified for patient treatment. 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 alteplase vial from the plastic molded capping attached to the bottom of the vial.
Reconstitution and Dilution: Alteplase should be reconstituted by aseptically adding to the vial, the appropriate volume of Sterile Water for Injection, USP [SWFI] (50mL for 50mg vials, 100mL for 100mg vials). It is important that alteplase be reconstituted only with Sterile Water for Injection, USP, without preservatives. Do not use Bacteriostatic Water for Injection. The reconstituted preparation results in a colorless to pale yellow transparent solution containing alteplase 1.0mg/mL at a pH of 7.3. The osmolality of this solution is approximately 215mOsm/kg.
Before further dilution or administration, parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. Because alteplase contains no preservatives, it should be reconstituted immediately before use (see Stability and Storage).
The reconstituted solution may be diluted further immediately before administration to yield concentrations as low as 0.5mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Excessive agitation during dilution should be avoided; mixing should be accomplished with gentle swirling and/or slow inversion. Do not use other infusion solutions e.g., Sterile Water for Injection, USP, or preservative containing solutions for further dilution.
No other medication should be added to alteplase solution. Solutions should be administered as described above. Unused infusion solution should be immediately discarded.
50 mg Vials: Using a large bore needle (e.g., 18gauge), and the accompanying 50mL Sterile Water for Injection, USP, direct the stream of Sterile Water for Injection, USP into the lyophilized cake. Do not use if vacuum is not present. Slight foaming upon reconstitution is not unusual; standing undisturbed for several minutes is usually sufficient to allow dissipation of any large bubbles. Excessive or vigorous shaking should be avoided.
100 mg Vials: Using the transfer device provided, the contents of the accompanying 100mL vial of Sterile Water for Injection, USP should be added to the contents of the 100mg vial of alteplase powder. Slight foaming upon reconstitution is not unusual; standing undisturbed for several minutes is usually sufficient to allow dissipation of any large bubbles. No vacuum is present in 100mg vials. Please refer to the accompanying instructions for Reconstitution and Administration of the 100mg vials: 1.Use aseptic technique throughout.
2.Remove the protective flip-caps from 1vial of alteplase and 1vial of Sterile Water for Injection, USP [SWFI].
3.Open the package containing the transfer device by peeling the paper label off the package.
4.Remove the protective cap from one end of the transfer device and keeping the vial of SWFI upright, insert the piercing pin vertically into the centre of the stopper of the vial of SWFI.
5.Remove the protective cap from the other end of the transfer device. Do not invert the vial of SWFI.
6.Holding the vial of alteplase upside-down, position it so that the centre of the stopper is directly over the exposed piercing pin of the transfer device.
7.Push the vial of alteplase down so that the piercing pin is inserted through the centre of the alteplase stopper.
8.Invert the 2vials so that the vial of alteplase is on the bottom (upright) and the vial of SWFI is upside-down, allowing the SWFI to flow down through the transfer device. Allow the entire contents of the vial of SWFI to flow into the alteplase vial (approximately 0.5mL of SWFI will remain in the diluent vial). Approximately 2minutes are required for this procedure.
9.Remove the transfer device and the empty SWFI vial from the alteplase vial. Safely discard both the transfer device and the empty diluent vial according to institutional procedures.
10.Swirl gently to dissolve the alteplase powder. Do not shake.
Stability and Storage: Lyophilized alteplase is stable up to the expiration date stamped on the vial when stored at controlled temperatures between 2and 30°C. Protect the lyophilized material during extended storage from excessive exposure to light.
Unused reconstituted alteplase (in the vial) may be stored at 2to 30°C for up to 8hours. After that time, any unused portion of the reconstituted material should be discarded. During the period of reconstitution and infusion, protection from light is not necessary.
Supplied / Packaging
50mg: Each vial of sterile, white to off-white, lyophilized powder contains: alteplase 50mg. Nonmedicinal ingredients: L-arginine, phosphoric acid, polysorbate 80. Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Vials of 50 mg with vacuum present. Boxes of 1vial of Activase rt-PA 50mg (29´10 6 IU), and 1vial of Sterile Water for Injection, USP 50 mL, for preparing a sterile solution of Activase rt-PA.
100mg: Each vial of sterile, white to off-white, lyophilized powder contains: alteplase 100mg. Nonmedicinal ingredients: L-arginine, phosphoric acid, polysorbate 80. Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Vials of 100 mg with no vacuum present. Boxes of 1vial of Activase rt-PA 100mg (58´10 6 IU), and 1vial of Sterile Water for Injection, USP 100 mL, and 1transfer device for preparing a sterile solution of Activase rt-PA.
Biological potency is determined by an in vitro clot lysis assay and is expressed in International Units (58´10 4IU/mg alteplase).
Lyophilized alteplase is stable up to the expiration date stamped on the vial when stored at controlled temperatures between 2and 30°C. Protect the lyophilized material during extended storage from excessive exposure to light.
50mg: Each vial of sterile, white to off-white, lyophilized powder contains: alteplase 50mg. Nonmedicinal ingredients: L-arginine, phosphoric acid, polysorbate 80. Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Vials of 50 mg with vacuum present. Boxes of 1vial of Activase rt-PA 50mg (29´10 6 IU), and 1vial of Sterile Water for Injection, USP 50 mL, for preparing a sterile solution of Activase rt-PA.
100mg: Each vial of sterile, white to off-white, lyophilized powder contains: alteplase 100mg. Nonmedicinal ingredients: L-arginine, phosphoric acid, polysorbate 80. Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Vials of 100 mg with no vacuum present. Boxes of 1vial of Activase rt-PA 100mg (58´10 6 IU), and 1vial of Sterile Water for Injection, USP 100 mL, and 1transfer device for preparing a sterile solution of Activase rt-PA.
Biological potency is determined by an in vitro clot lysis assay and is expressed in International Units (58´10 4IU/mg alteplase).
Lyophilized alteplase is stable up to the expiration date stamped on the vial when stored at controlled temperatures between 2and 30°C. Protect the lyophilized material during extended storage from excessive exposure to light.
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Brand Name
Activase Rt-PA (Acute Ischemic Stroke)
Activase Rt-PA (Acute Ischemic Stroke)
Generic Name
Alteplase
Alteplase
General Indications
Fibrinolytic Agent
Fibrinolytic Agent
