Activase (Alteplase)

ACTIVASE® rt-PA

Roche

Alteplase

Fibrinolytic Agent

Action And Clinical Pharmacology: Alteplase is a serine protease which has the property of fibrin-enhanced conversion of plasminogen to plasmin. It 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 (20 to 30%) in circulating fibrinogen. Decreases in plasminogen and a2-antiplasmin are also evident.

Alteplase is cleared rapidly from circulating 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 acute myocardial infarction (AMI). The plasma clearance of alteplase is approximately 500 mL/min. The clearance is mediated primarily by the liver.

An occlusive 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.

Acute Myocardial Infarction Patients: Two alteplase dose regimens have been studied in patients experiencing AMI: accelerated infusion, and 3-hour infusion. The comparative efficacy of these 2 regimens has not been evaluated.

90-Minute Accelerated Infusion in Patients with Acute Myocardial Infarction: Accelerated infusion of alteplase was studied in an international, multicentre trial (GUSTO) where 41 021 patients with acute myocardial infarction were randomized to 4 thrombolytic regimens: accelerated infusion of alteplase.

Subgroup analysis of patients by age, infarct location, and time from symptom onset to thrombolytic treatment showed consistently lower 30-day mortality for the group receiving the accelerated infusion of alteplase. 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 group receiving the accelerated infusion of alteplase, 2.8% for streptokinase (i.v. heparin), and 3.2% for streptokinase (s.c. heparin); the incidence of combined 30-day mortality or nonfatal stroke was 20.6% for accelerated infusion of alteplase, 21.5% for streptokinase (i.v. heparin), and 22.0% for streptokinase (s.c. heparin).

3-Hour Infusion in Patients with Acute Myocardial Infarction: In patients studied with coronary angiography prior to and following infusion of alteplase, the use of alteplase resulted in reperfusion of documented obstructed vessels within 90 minutes after the commencement of thrombolytic therapy in approximately 70% of patients. In 2 studies involving 145 patients, alteplase produced reperfusion in 73% of patients who received 70 to 100 mg (40.6 to 58´10IU) over 90 minutes. In 2 double blind randomized controlled trials in patients with AMI, the patients infused with 80 to 100 mg of alteplase experienced improved ventricular function and reduced incidence of clinical congestive heart failure compared to those treated with placebo.

In a double-blind study involving 5 013 patients (ASSET Study) where patients were infused with either alteplase or placebo within 5 hours of onset of symptoms of AMI, improved 30-day survival was shown in patients receiving alteplase compared to placebo. At 1 month, the overall mortality rates were 7.2% for the alteplase-treated group and 9.8% for the placebo-treated group (p=0.001). This benefit was maintained at 6 months (10.4% and 13.1% for alteplase and placebo-treated patients respectively, p=0.008).

In the LATE study involving 5 711 patients where patients were infused with either alteplase (100 mg over 3 hours) or placebo within 6 to 24 hours of onset of AMI symptoms, the 35-day mortality rates were 8.9% for Activase rt-PA treated patients and 10.3% for placebo-treated patients (p=not significant). Prespecified survival analysis according to treatment within 12 hours of symptom onset showed a significant reduction in mortality for the alteplase treated patients, 8.9% versus 12.0% for the placebo treated patients (p=0.0229).

Indications And Clinical Uses: For i.v. use in adults for: the lysis of suspected occlusive coronary artery thrombi associated with evolving transmural myocardial infarction; and the reduction of mortality associated with AMI, the improvement of ventricular function following AMI and the reduction in the incidence of congestive heart failure.

Treatment should be initiated as soon as possible after the onset of acute myocardial symptoms. Greater benefit appears to be associated with earlier treatment of alteplase, following the onset of symptoms.

Alteplase is effective in patients in whom therapy is initiated within 6 hours of onset of symptoms for the accelerated infusion regimen or up to 12 hours after onset of symptoms for the 3-hour infusion regimen. The GUSTO study was designed to enrol patients within a 6-hour period following the onset of myocardial infarct symptoms. The data available from this trial are insufficient to support a recommendation for use of the accelerated infusion regimen in patients presenting more than 6 hours after the onset of symptoms.

Contra-Indications: Because thrombolytic therapy increases the risk of bleeding, alteplase is contraindicated in the following situations: active internal bleeding; history of stroke; patients receiving other i.v. thrombolytic agents; recent (within 2 months) intracranial, or intraspinal surgery or trauma (see Warnings); intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diathesis; severe uncontrolled hypertension, i.e., diastolic BP³110 mm Hg and/or systolic BP³180 mm Hg; recent traumatic cardiopulmonary resuscitation; recent severe trauma.

Manufacturers’ Warnings In Clinical States: Bleeding: The most common complication encountered during therapy with alteplase is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into 2 broad categories: internal bleeding involving the gastrointestinal tract, genitourinary tract, respiratory tract, retroperitoneal or intracranial sites; superficial or surface bleeding, observed mainly at invaded or disturbed sites (e.g., venous cutdowns, arterial punctures, sites of recent surgical intervention).

The concomitant use of heparin anticoagulation contributes to the risk of bleeding.

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 punctures 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 30 minutes, 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 10 days) 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 (with 10 days); recent trauma (within 10 days); a history or clinical evidence of hypertensive disease in a patient over 70 years old; advanced age, e.g., over 75 years 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.

Arrhythmias: Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) are not different from those often seen in the ordinary course of AMI and may be managed with standard antiarrhythmic measures. It is recommended that antiarrhythmic therapy for bradycardia and/or ventricular irritability be available when infusions of alteplase are administered.

Use of Antithrombotics: ASA and heparin may be administered concomitantly with and following infusions of alteplase. Because either heparin, ASA or alteplase alone may cause bleeding complications, careful monitoring for bleeding is advised, especially at arterial puncture sites.

Precautions: General: Alteplase should be administered in a hospital setting where the appropriate diagnostic and monitoring techniques are readily available.

Routine management of myocardial infarction should not be deferred after evidence of successful thrombolysis is seen. Evaluation and management of underlying atherosclerotic heart disease should be carried out as clinically indicated.

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 (150 to 200 units/mL) can to some extent mitigate this phenomenon.

Geriatrics: The risks of therapy may be increased in the elderly (see Pharmacology, Warnings and Adverse Effects).

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.

Adverse Reactions: Bleeding: The most frequent adverse reaction associated with alteplase is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into 2 broad categories: internal bleeding, involving the gastrointestinal tract, genitourinary tract, respiratory tract, retroperitoneal or intracranial sites; superficial or surface bleeding, observed mainly at invaded or disturbed sites (e.g., venous cutdowns, arterial punctures, sites of recent surgical intervention).

The incidence of all strokes for the accelerated alteplase regimen in the GUSTO trial 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. Data from previous trials utilizing a 3-hour infusion indicates that the incidence of total stroke in 6 randomized double-blind placebo controlled trials was 1.2% (37/3 161) in alteplase-treated patients (£100 mg) compared with 0.9% (27/3 092) in placebo-treated patients.

Although the incidence of all strokes, as well as that for hemorrhagic stroke, increased with increasing age, treatment with accelerated regimen of alteplase was still shown to reduce mortality in older patients. 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 accelerated regimen of alteplase group, 2.8% for streptokinase (i.v. heparin), and 3.2% for streptokinase (s.c. heparin). However, combined 30-day mortality or nonfatal stroke was 20.6% for accelerated regimen of alteplase, 21.5% for streptokinase (i.v. heparin) and 22.0% for streptokinase (s.c. heparin) in the GUSTO study.

The following incidence of significant internal bleeding (estimated as 250 mL blood loss) has been reported in studies involving over 1 300 patients treated at all doses of alteplase, administered as a 3-hour infusion regimen: gastrointestinal 5%, genitourinary 4%.

The following incidence of moderate or severe bleeding was reported when £100 mg alteplase was administered by accelerated infusion to >10 000 patients [GUSTO study]: gastrointestinal 1.5%, genitourinary 0.5%.

Incidence of £1% of ecchymosis, retroperitoneal bleeding, epistaxis and gingival bleeding has been reported in clinical studies involving alteplase.

The incidence of intracranial bleeding in patients treated with up to 120 mg alteplase (3-hour infusion) has been 0.4%. At doses in excess of 120 mg (120 to 180 mg) the incidence of intracranial bleeding increased to 1.3%. The incidence of intracranial bleeding in patients treated 100 mg alteplase (accelerated infusion, weight adjusted) was 0.7%. The maximum total dose of alteplase should not exceed 100 mg.

Death and permanent disability have been reported in patients who have experienced stroke and other serious bleeding episodes.

Allergic Reactions: Allergic-type reactions, e.g., anaphylactoid reaction, laryngeal edema, rash and urticaria have been reported very rarely.

Other Adverse Reactions: Patients with myocardial infarction can experience disease-related events such as cardiogenic shock, arrhythmias, pulmonary edema, heart failure, cardiac arrest, recurrent ischemia, reinfarction, myocardial rupture, mitral regurgitation, pericardial effusion, pericarditis, cardiac tamponade, venous thrombosis and embolism, and electromechanical dissociation. These events may lead to death. Other adverse reactions have been reported, principally nausea and/or vomiting, hypotension, and fever. These reactions are frequent sequelae of myocardial infarction and may or may not be attributable to alteplase therapy.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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.

Dosage And Administration: 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.

Acute Myocardial Infarction: Administer alteplase as soon as possible after the onset of symptoms.

There are 2 dose regimens for alteplase for use in the management of AMI. The comparative efficacy of these 2 regimens has not been evaluated.

90-Minute Accelerated Infusion: The recommended total dose is based upon patient weight, not to exceed 100 mg. For patients weighing >67 kg, the recommended dose is 100 mg, administered as a 15 mg i.v. bolus, followed by 50 mg infused over 30 minutes and then 35 mg infused over the next 60 minutes.

Preparation and Administration: The alteplase dose administered by accelerated infusion may be prepared and administered as follows: A. The bolus dose may be prepared in one of the following ways: 1. By removing 15 mL from the vial of reconstituted (1 mg/mL) alteplase using a syringe and needle. For 50 mg vials, the syringe should not be primed with air and the needle should be inserted into the alteplase vial stopper. If the 100 mg vial is used, the needle should be inserted away from the puncture mark made by the transfer device. 2. By removing 15 mL from a port (second injection site) on the infusion line after the infusion set is primed. 3. By programming an infusion pump to deliver a 15 mL (1 mg/mL) bolus at the initiation of the infusion. B. The remainder of the alteplase dose may be administered as follows: 50 mg vials: Administer using either a polyvinyl chloride bag or glass vial and infusion set. 100 mg vials: 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 vial of alteplase from the plastic molded capping attached to the bottom of the vial.

3-Hour Infusion: The recommended dose is 100 mg administered as 60 mg (34.8´10IU) in the first hour, of which 6 to 7 mg is administered as a bolus over the first 1 to 2 minutes and the remainder is administered by continuous infusion, 20 mg (11.6´10IU) by continuous infusion during the second hour, and 20 mg (11.6´10IU) by continuous infusion over the following 1 to 4 hours.

Anticoagulation During and After Treatment with Alteplase: To date, heparin has been administered concomitantly in more than 90% of patients given alteplase. Adjunctive i.v. heparin administration is recommended to obtain a therapeutic partial thromboplastin time (PTT). The infusion of heparin should be initiated prior to the termination of the infusion of alteplase.

Reconstitution and Dilution: Alteplase should be reconstituted by aseptically adding to the vial, the appropriate volume of Sterile Water for Injection, USP (50 mL for 50 mg vials, 100 mL for 100 mg 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 mg/mL at a pH of 7.3. The osmolality of this solution is approximately 215 mOsm/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 0.5 mg/mL in 0.9% Sodium Chloride for Injection, USP or 5% Dextrose for 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., 18 gauge), and the accompanying 50 mL 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 100 mL vial of Sterile Water for Injection, USP should be added to the contents of the 100 mg 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 100 mg vials. Please refer to the accompanying instructions for Reconstitution and Administration of the 100 mg vials:

1. Use aseptic technique throughout.

2. Remove the protection flip-caps from 1 vial of alteplase and 1 vial of Sterile Water for Injection, USP.

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 Sterile Water for Injection upright, insert the piercing pin vertically into the centre of the stopper of the vial of Sterile Water for Injection.

5. Remove the protective cap from the other end of the transfer device. Do not invert the vial of Sterile Water for Injection.

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 2 vials so that the vial of alteplase is on the bottom (upright) and the vial of Sterile Water for Injection is upside-down, allowing the Sterile Water for Injection to flow down through the transfer device. Allow the entire contents of the vial of Sterile Water for Injection to flow into the alteplase vial (approximately 0.5 mL of Sterile Water for Injection will remain in the diluent vial). Approximately 2 minutes are required for this procedure.

9. Remove the transfer device and the empty Sterile Water for Injection 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 2 and 30°C. Protect the lyophilized material during extended storage from excessive exposure to light.

Unused reconstituted alteplase (in the vial) may be stored at 2 to 30°C for up to 8 hours. 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.

Availability And Storage: 50 mg: Each vial of sterile, lyophilized powder contains: alteplase 50 mg. 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 1 vial of Activase rt-PA 50 mg (29´10IU), and 1 vial of Sterile Water for Injection, USP 50 mL, for preparing a sterile solution of Activase rt-PA.

100 mg: Each vial of sterile, lyophilized powder contains: alteplase 100 mg. 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 1 vial of Activase rt-PA 100 mg (58 ´ 10IU) and 1 vial of Sterile Water for Injection, USP 100 mL, and 1 transfer 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´10IU/mg alteplase).

ACTIVASE® rt-PA Roche Alteplase Fibrinolytic Agent

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