Name: Activase I.V.
- Activase I.V. 100 mg
- Activase I.V. injection
- Activase I.V. dosage
- Activase I.V. drug
- Activase I.V. 50 mg
Activase (Alteplase) is a tissue plasminogen activator produced by recombinant DNA technology. It is a sterile, purified glycoprotein of 527 amino acids. It is synthesized using the complementary DNA (cDNA) for natural human tissue-type plasminogen activator obtained from a human melanoma cell line. The manufacturing process involves the secretion of the enzyme alteplase into the culture medium by an established mammalian cell line (Chinese Hamster Ovary cells) into which the cDNA for alteplase has been genetically inserted. Fermentation is carried out in a nutrient medium containing the antibiotic gentamicin, 100 mg/L. However, the presence of the antibiotic is not detectable in the final product.
Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment.
Activase is a sterile, white to off-white, lyophilized powder for intravenous administration after reconstitution with Sterile Water for Injection, USP.
Biological potency is determined by an in vitro clot lysis assay and is expressed in International Units as tested against the WHO standard. The specific activity of Activase is 580,000 IU/mg.
Activase is an enzyme (serine protease) which has the property of fibrin-enhanced conversion of plasminogen to plasmin. It produces limited conversion of plasminogen in the absence of fibrin. When introduced into the systemic circulation at pharmacologic concentration, Activase binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin. This initiates local fibrinolysis with limited systemic proteolysis. Following administration of 100 mg Activase, there is a decrease (16%-36%) in circulating fibrinogen. 1,2 In a controlled trial, 8 of 73 patients (11%) receiving Activase (1.25 mg/kg body weight over 3 hours) experienced a decrease in fibrinogen to below 100 mg/dL. 2
The clearance of Alteplase in AMI patients has shown that it is rapidly cleared from the plasma with an initial half-life of less than 5 minutes. There is no difference in the dominant initial plasma half-life between the 3-Hour and accelerated regimens for AMI. The plasma clearance of Alteplase is 380-570 mL/min. 3,4 The clearance is mediated primarily by the liver. The initial volume of distribution approximates plasma volume.
Acute Myocardial Infarction (AMI) Patients
Coronary occlusion due to a thrombus is present in the infarct-related coronary artery in approximately 80% of patients experiencing a transmural myocardial infarction evaluated within 4 hours of onset of symptoms. 5,6
Two Activase dose regimens have been studied in patients experiencing acute myocardial infarction. (Please see DOSAGE AND ADMINISTRATION .) The comparative efficacy of these two regimens has not been evaluated.
Accelerated Infusion in AMI Patients
Accelerated infusion of Activase was studied in an international, multi-center trial (GUSTO) that randomized 41,021 patients with acute myocardial infarction to four thrombolytic regimens. Entry criteria included onset of chest pain within 6 hours of treatment and ST-segment elevation of ECG. The regimens included accelerated infusion of Activase (</= 100 mg over 90 minutes, see DOSAGE AND ADMINISTRATION ) plus intravenous (IV) heparin (accelerated infusion of Alteplase, n=10,396), or the Kabikinase brand of Streptokinase (1.5 million units over 60 minutes) plus IV heparin (SK [IV], n=10,410), or Streptokinase (as above) plus subcutaneous (SQ) heparin (SK [SQ], n=9841). A fourth regimen combined Alteplase and Streptokinase. Aspirin and heparin use was directed by the GUSTO study protocol as follows: All patients were to receive 160 mg chewable aspirin administered as soon as possible, followed by 160-325 mg daily. IV heparin was directed to be a 5000 U IV bolus initiated as soon as possible, followed by a 1000 U/hour continuous IV infusion for at least 48 hours; subsequent heparin therapy was at the discretion of the attending physician. SQ heparin was directed to be 12,500 U administered 4 hours after initiation of SK therapy, followed by 12,500 U twice daily for 7 days or until discharge, whichever came first. Many of the patients randomized to receive SQ heparin received some IV heparin, usually in response to recurrent chest pain and/or the need for a medical procedure. Some received IV heparin on arrival to the emergency room prior to enrollment and randomization.
Results for the primary endpoint of the study, 30-day mortality, are shown in Table 1. The incidence of 30-day mortality for accelerated infusion of Alteplase was 1.0% lower than for SK (IV) and 1.0% lower than for SK (SQ). The secondary endpoints of combined 30-day mortality or nonfatal stroke, and 24-hour mortality, as well as the safety endpoints of total stroke and intracerebral hemorrhage are also shown in Table 1. The incidence of combined 30-day mortality or nonfatal stroke for the Alteplase accelerated infusion was 1.0% lower than for SK (IV) and 0.8% lower than for SK (SQ).
Subgroup analysis of patients by age, infarct location, time from symptom onset to thrombolytic treatment, and treatment in the U.S. or elsewhere showed consistently lower 30-day mortality for the Alteplase accelerated infusion group. For patients who were over 75 years of age, a predefined subgroup consisting of 12% of patients enrolled, the incidence of stroke was 4.0% for the Alteplase accelerated infusion group, 2.8% for SK (IV), and 3.2% for SK (SQ); the incidence of combined 30-day mortality or nonfatal stroke was 20.6% for accelerated infusion of Alteplase, 21.5% for SK (IV), and 22.0% for SK (SQ).
An angiographic substudy of the GUSTO trial provided data on infarct-related artery patency. Table 2 presents 90-minute, 180-minute, 24-hour, and 5-7 day patency values by TIMI flow grade for the three treatment regimens. Reocclusion rates were similar for all three treatment regimens.
The exact relationship between coronary artery patency and clinical activity has not been established.
The safety and efficacy of the accelerated infusion of Alteplase have not been evaluated using antithrombotic or antiplatelet regimens other than those used in the GUSTO trial.
3-Hour Infusion in AMI Patients
In patients studied in a controlled trial with coronary angiography at 90 and 120 minutes following infusion of Activase, infarct artery patency was observed in 71% and 85% of patients (n=85), respectively. 2 In a second study, where patients received coronary angiography prior to and following infusion of Activase within 6 hours of the onset of symptoms, reperfusion of the obstructed vessel occurred within 90 minutes after the commencement of therapy in 71% of 83 patients. 1
The exact relationship between coronary artery patency and clinical activity has not been established.
In a double-blind, randomized trial (138 patients) comparing Activase to placebo, patients infused with Activase within 4 hours of onset of symptoms experienced improved left ventricular function at Day 10 compared to the placebo group, when ejection fraction was measured by gated blood pool scan (53.2% vs 46.4%, p=0.018). Relative to baseline (Day 1) values, the net changes in ejection fraction were +3.6% and -4.7% for the treated and placebo groups, respectively (p=0.0001). Also documented was a reduced incidence of clinical congestive heart failure in the treated group (14%) compared to the placebo group (33%) (p=0.009). 7
In a double-blind, randomized trial (145 patients) comparing Activase to placebo, patients infused with Activase within 2.5 hours of onset of symptoms experienced improved left ventricular function at a mean of 21 days compared to the placebo group, when ejection fraction was measured by gated blood pool scan (52% vs 48%, p=0.08) and by contrast ventriculogram (61% vs 54%, p=0.006). Although the contribution of Activase alone is unclear, the incidence of nonischemic cardiac complications when taken as a group (i.e., congestive heart failure, pericarditis, atrial fibrillation, and conduction disturbance) was reduced when compared to those patients treated with placebo (p < 0.01). 8
In a double-blind, randomized trial (5013 patients) comparing Activase to placebo (ASSET study), patients infused with Activase within 5 hours of the onset of symptoms of acute myocardial infarction experienced improved 30-day survival compared to those treated with placebo. At 1 month, the overall mortality rates were 7.2% for the Activase-treated group and 9.8% for the placebo-treated group (p=0.001). 9,10 This benefit was maintained at 6 months for Activase-treated patients (10.4%) compared to those treated with placebo (13.1%, p=0.008). 10
In a double-blind, randomized trial (721 patients) comparing Activase to placebo, patients infused with Activase within 5 hours of the onset of symptoms experienced improved ventricular function 10-22 days after treatment compared to the placebo group, when global ejection fraction was measured by contrast ventriculography (50.7% vs 48.5%, p=0.01). Patients treated with Activase had a 19% reduction in infarct size, as measured by cumulative release of HBD ((alpha)-hydroxybutyrate dehydrogenase) activity compared to placebo-treated patients (p=0.001). Patients treated with Activase had significantly fewer episodes of cardiogenic shock (p=0.02), ventricular fibrillation (p < 0.04) and pericarditis (p=0.01) compared to patients treated with placebo. Mortality at 21 days in Activase-treated patients was reduced to 3.7% compared to 6.3% in placebo-treated patients (1-sided p=0.05). 11 Although these data do not demonstrate unequivocally a significant reduction in mortality for this study, they do indicate a trend that is supported by the results of the ASSET study.
Acute Ischemic Stroke Patients
Two placebo-controlled, double-blind trials (The NINDS t-PA Stroke Trial, Part 1 and Part 2) have been conducted in patients with acute ischemic stroke. 12 Both studies enrolled patients with measurable neurological deficit who could complete screening and begin study treatment within 3 hours from symptom onset. A cranial computerized tomography (CT) scan was performed prior to treatment to rule out the presence of intracranial hemorrhage (ICH). Patients were also excluded for the presence of conditions related to risks of bleeding (see CONTRAINDICATIONS ), for minor neurological deficit, for rapidly improving symptoms prior to initiating study treatment, or for blood glucose of < 50 mg/dL or > 400 mg/dL.
Patients were randomized to receive either 0.9 mg/kg Activase (maximum of 90 mg), or placebo. Activase was administered as a 10% initial bolus over 1 minute followed by continuous intravenous infusion of the remainder over 60 minutes (see DOSAGE AND ADMINISTRATION ). In patients without recent use of oral anticoagulants or heparin, study treatment was initiated prior to the availability of coagulation study results. However, the infusion was discontinued if either a pretreatment prothrombin time (PT) > 15 seconds or an elevated activated partial thromboplastin time (aPTT) was identified. Although patients with or without prior aspirin use were enrolled, administration of anticoagulants and antiplatelet agents was prohibited for the first 24 hours following symptom onset.
The initial study (NINDS-Part 1, n=291) evaluated neurological improvement at 24 hours after stroke onset. The primary endpoint, the proportion of patients with a 4 or more point improvement in the National Institutes of Health Stroke Scale (NIHSS) score or complete recovery (NIHSS score = 0), was not significantly different between treatment groups. A secondary analysis suggested improved 3-month outcome associated with Activase treatment using the following stroke assessment scales: Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale, and the NIHSS.
A second study (NINDS-Part 2, n=333) assessed clinical outcome at 3 months as the primary outcome. A favorable outcome was defined as minimal or no disability using the four stroke assessment scales: Barthel Index (score >/= 95), Modified Rankin Scale (score </= 1), Glasgow Outcome Scale (score = 1), and NIHSS (score </= 1). The results comparing Activase- and placebo-treated patients for the four outcome scales together (Generalized Estimating Equations) and individually are presented in Table 3. In this study, depending upon the scale, the favorable outcome of minimal or no disability occurred in at least 11 per 100 more patients treated with Activase than those receiving placebo. Secondary analyses demonstrated consistent functional and neurological improvement within all four stroke scales as indicated by median scores. These results were highly consistent with the 3-month outcome treatment effects observed in the Part 1 study.
The incidences of all-cause 90-day mortality, ICH, and new ischemic stroke following Activase treatment compared to placebo are presented in Table 4 as a combined safety analysis (n=624) for Parts 1 and 2. These data indicated a significant increase in ICH following Activase treatment, particularly symptomatic ICH within 36 hours. In Activase-treated patients, there were no increases compared to placebo in the incidences of 90-day mortality or severe disability.
In a prespecified subgroup analysis in patients receiving aspirin prior to onset of stroke symptoms, there was preserved favorable outcome for Activase-treated patients.
Exploratory, multivariate analyses of both studies combined (n=624) to investigate potential predictors of ICH and treatment effect modifiers were performed. In Activase-treated patients presenting with severe neurological deficit (e.g., NIHSS > 22) or of advanced age (e.g., > 77 years of age), the trends toward increased risk for symptomatic ICH within the first 36 hours were more prominent. Similar trends were also seen for total ICH and for all-cause 90-day mortality in these patients. When risk was assessed by the combination of death and severe disability in these patients, there was no difference between placebo and Activase groups. Analyses for efficacy suggested a reduced but still favorable clinical outcome for Activase-treated patients with severe neurological deficit or advanced age at presentation.
Pulmonary Embolism Patients
In a comparative randomized trial (n=45), 13 59% of patients (n=22) treated with Activase (100 mg over 2 hours) experienced moderate or marked lysis of pulmonary emboli when assessed by pulmonary angiography 2 hours after treatment initiation. Activase-treated patients also experienced a significant reduction in pulmonary embolism-induced pulmonary hypertension within 2 hours of treatment (p=0.003). Pulmonary perfusion at 24 hours, as assessed by radionuclide scan, was significantly improved (p=0.002).
The most frequent adverse reaction associated with Activase in all approved indications is bleeding (see WARNINGS ). 15,16
Should serious bleeding in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial) occur, Activase therapy should be discontinued immediately, along with any concomitant therapy with heparin. Death and permanent disability are not uncommonly reported in patients that have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.
In the GUSTO trial for the treatment of acute myocardial infarction, using the accelerated infusion regimen the incidence of all strokes for the Activase-treated patients was 1.6%, while the incidence of nonfatal stroke was 0.9%. The incidence of hemorrhagic stroke was 0.7%, not all of which were fatal. The incidence of all strokes, as well as that for hemorrhagic stroke, increased with increasing age (see CLINICAL PHARMACOLOGY : Accelerated Infusion in AMI Patients ). Data from previous trials utilizing a 3-hour infusion of </= 100 mg indicated that the incidence of total stroke in six randomized, double-blind, placebo-controlled trials 2,7-11,17 was 1.2% (37/3161) in Alteplase-treated patients compared with 0.9% (27/3092) in placebo-treated patients.
For the 3-hour infusion regimen, the incidence of significant internal bleeding (estimated as > 250 cc blood loss) has been reported in studies in over 800 patients. These data do not include patients treated with the Alteplase accelerated infusion.
The incidence of intracranial hemorrhage (ICH) in acute myocardial infarction patients treated with Activase is as follows:
These data indicate that a dose of 150 mg of Activase should not be used in the treatment of AMI because it has been associated with an increase in intracranial bleeding. 18
For acute massive pulmonary embolism, bleeding events were consistent with the general safety profile observed with Activase in acute myocardial infarction patients receiving the 3-hour infusion regimen.
The incidence of ICH, especially symptomatic ICH, in patients with acute ischemic stroke was higher in Activase-treated patients than placebo patients (see CLINICAL PHARMACOLOGY ).
A study of another alteplase product, Actilyse, in acute ischemic stroke, suggested that doses greater than 0.9 mg/kg may be associated with an increased incidence of ICH. 19 Doses greater than 0.9 mg/kg (maximum 90 mg) should not be used in the management of acute ischemic stroke.
Bleeding events other than ICH were noted in the studies of acute ischemic stroke and were consistent with the general safety profile of Activase. In The NINDS t-PA Stroke Trial (Parts 1 and 2), the frequency of bleeding requiring red blood cell transfusions was 6.4% for Activase-treated patients compared to 3.8% for placebo (p=0.19, using Mantel-Haenszel Chi-Square).
Fibrin which is part of the hemostatic plug formed at needle puncture sites will be lysed during Activase therapy. Therefore, Activase therapy requires careful attention to potential bleeding sites, e.g., catheter insertion sites, and arterial puncture sites.
Allergic-type reactions, e.g., anaphylactoid reaction, laryngeal edema, orolingual angioedema, rash, and urticaria have been reported. A cause and effect relationship to Activase therapy has not been established. When such reactions occur, they usually respond to conventional therapy.
There have been postmarketing reports of orolingual angioedema associated with the use of Activase. Most reports were of patients treated for acute ischemic stroke, some reports were of patients treated for acute myocardial infarctions (see PRECAUTIONS: General). Many of these patients received concomitant angiotensin-converting enzyme inhibitors (see PRECAUTIONS: Drug Interactions). Most cases resolved with prompt treatment; there have been rare fatalities as a result of upper airway hemorrhage from intubation trauma.
Other Adverse Reactions
The following adverse reactions have been reported among patients receiving Activase in clinical trials and in postmarketing experience. These reactions are frequent sequelae of the underlying disease and the effect of Activase on the incidence of these events is unknown.
Use in Acute Myocardial Infarction: Arrhythmias, AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia, myocardial reinfarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema. These events may be life threatening and may lead to death. Nausea and/or vomiting, hypotension and fever have also been reported.
Use in Pulmonary Embolism: Pulmonary reembolization, pulmonary edema, pleural effusion, thromboembolism, hypotension. These events may be life threatening and may lead to death. Fever has also been reported.
Use in Acute Ischemic Stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke. These events may be life threatening and may lead to death.
Activase (Alteplase) is supplied as a sterile, lyophilized powder in 50 mg vials containing vacuum and in 100 mg vials without vacuum.
Each 50 mg Activase vial (29 million IU) is packaged with diluent for reconstitution (50 mL Sterile Water for Injection, USP): NDC 50242-044-13.
Each 100 mg Activase vial (58 million IU) is packaged with diluent for reconstitution (100 mL Sterile Water for Injection, USP), and one transfer device: NDC 50242-085-27.
Store lyophilized Activase at controlled room temperature not to exceed 30°C (86°F), or under refrigeration (2-8°C/36-46°F). Protect the lyophilized material during extended storage from excessive exposure to light.
Do not use beyond the expiration date stamped on the vial.
- Mueller H, Rao AK, Forman SA, et al. Thrombolysis in myocardial infarction (TIMI): comparative studies of coronary reperfusion and systemic fibrinogenolysis with two forms of recombinant tissue-type plasminogen activator. J Am Coll Cardiol. 1987;10:479-90.
- Topol EJ, Morriss DC, Smalling RW, et al. A multicenter, randomized, placebo-controlled trial of a new form of intravenous recombinant tissue-type plasminogen activator (Activase) in acute myocardial infarction. J Am Coll Cardiol. 1987;9:1205-13.
- Seifried E, Tanswell P, Ellbrück D, et al. Pharmacokinetics and haemostatic status during consecutive infusions of recombinant tissue-type plasminogen activator in patients with acute myocardial infarction. Thromb Haemostas. 1989;61:497-501.
- Tanswell P, Tebbe U, Neuhaus K-L, et al. Pharmacokinetics and fibrin specificity of Alteplase during accelerated infusions in acute myocardial infarction. J Am Coll Cardiol. 1992;19:1071-5.
- De Wood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. New Engl J Med. 1980;303:897-902.
- Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in myocardial infarction (TIMI) trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation. 1987;76(1):142-54.
- Guerci AD, Gerstenblith G, Brinker JA, et al. A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective coronary angioplasty. New Engl J Med. 1987;317:1613-18.
- O'Rourke M, Baron D, Keogh A, et al. Limitation of myocardial infarction by early infusion of recombinant tissue-plasminogen activator. Circulation. 1988;77:1311-15.
- Wilcox RG, von der Lippe G, Olsson CG, et al. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction: ASSET. Lancet. 1988;2:525-30.
- Hampton JR, The University of Nottingham. Personal communication.
- Van de Werf F, Arnold AER, et al. Effect of intravenous tissue-plasminogen activator on infarct size, left ventricular function and survival in patients with acute myocardial infarction. Br Med J. 1988;297:1374-9.
- The National Institute of Neurological Disorders and Stroke t-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. New Engl J Med. 1995;333:1581-7.
- Goldhaber SZ, Kessler CM, Heit J, et al. A randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet. 1988;2:293-8.
- Aylward P, Wilcox R, Horgan J, White H, Granger C, Califf R, et al. for the GUSTO-I Investigators. Relation of increased arterial blood pressure to mortality and stroke in the context of contemporary thrombolytic therapy for acute myocardial infarction: a randomized trial. Ann Int Med. 1996;125:891-900.
- Califf RM, Topol EJ, George BS, et al. Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of acute myocardial infarction. Am J Med. 1988;85:353-9.
- Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction: results from the thrombolysis in myocardial infarction (TIMI), Phase II trial. Ann Int Med. 1991;115(4):256-65.
- National Heart Foundation of Australia Coronary Thrombolysis Group. Coronary thrombolysis and myocardial infarction salvage by tissue plasminogen activator given up to 4 hours after onset of myocardial infarction. Lancet. 1988;1:203-7.
- Gore JM, Sloan M, Price TR, et al. and the TIMI Investigators. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the thrombolysis in myocardial infarction study. Circulation. 1991;83:448-59.
- Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. for the ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA . 1995;274:1017-25.
Activase, (Alteplase) 4800511
Manufactured by Revision Date October 2002
GENENTECH, INC. FDA Approval Date May 2002
1 DNA Way © 2002 Genentech, Inc.
South San Francisco, CA 94080-4990
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