Eminase (Anistreplase)

EMINASE®

Roberts

Anistreplase

Fibrinolytic Agent

Action And Clinical Pharmacology: Anistreplase is an inactive derivative of a fibrinolytic (thrombolytic) enzyme composed of streptokinase and lys-plasminogen in which the catalytic center of the enzymatic complex is temporarily blocked by a p-anisoyl group.

Anistreplase has high fibrin-binding ability; the lys-plasminogen component of anistreplase has greater fibrin affinity than that of native glu-plasminogen.

Activation of anistreplase to lys-plasminogen-streptokinase occurs by a first order, hydrolytic process, in blood or in the thrombus, with release of the p-anisoyl group by deacylation. The nonenzymatic deacylation process starts immediately after i.v. administration of anistreplase and progresses with a half-life of about 2 hours, as estimated in vitro in human blood.

Anistreplase is a plasminogen activator and, therefore, exerts its fibrinolytic activity by converting plasminogen into its proteolytically active form, plasmin. Plasmin then digests the insoluble fibrin network which stabilizes a thrombus, into smaller, soluble fibrin degradation products which results in thrombolysis.

The hypotensive effect of streptokinase plasminogen was compared with anistreplase in beagle dogs given equivalent doses by rapid i.v. injection. Streptokinase-plasminogen produced a pronounced hypotensive effect within 1 to 3 minutes after administration whereas anistreplase had no hypotensive effect.

After i.v. administration of anistreplase by single injection to patients, the circulating half-life of fibrinolytic activity resulting from anistreplase (mean of 94 minutes; range of 70 to 120 minutes) is longer than that after i.v. infusion of streptokinase (about 20 minutes). The p-anisoyl group in anistreplase permits i.v. administration over 2 to 5 minutes, slows the loss of circulating fibrinolytic activity in the bloodstream and, hence, prolongs the duration of thrombolytic action.

A number of controlled clinical studies have been performed with anistreplase to demonstrate benefit. Heparin anticoagulation was administered to all patients routinely following (about 4 to 6 hours) dosing with anistreplase.

Randomized, controlled studies have demonstrated that anistreplase reduces mortality when administered within 6 hours of the onset of the symptoms of acute myocardial infarction (AMI). The benefit of mortality reduction occurs acutely and is maintained for at least 1 year.

In a randomized, double blind study of 1 258 patients (AIMS trial), at 30 days postinfarction, mortality was decreased (47.2%, p=0.0001) in patients receiving anistreplase as compared with placebo. At 1 year, the reduction in mortality was maintained (38%, p=0.001). The incidence of heart failure was less in patients treated with anistreplase (17.9%) compared with patients who received placebo (23.3%). In a German multicenter, randomized, controlled trial involving 313 patients (162 received anistreplase, 151 received heparin), reduction in mortality, similar to that obtained in the AIMS trial, was observed (56%, p=0.032).

In a double-blind, randomized trial of anistreplase compared with heparin bolus (112 received anistreplase, 119 received heparin), left ventricular function was improved and infarction size reduced.
In randomized, comparative studies, reperfusion rates of between 50 and 68% have been reported in patients receiving anistreplase within 6 hours of symptom onset. However, for maximum rates of reperfusion, treatment should be initiated as soon as possible after onset of symptoms.

In 2 studies, anistreplase and intracoronary (IC) streptokinase were compared in patients with angiographically proven coronary artery occlusion. Reperfusion occurred about 45 minutes after the start of therapy for both treatment groups. When therapy was initiated within 4 hours of onset of AMI symptoms, reperfusion rates of 59% (n=87) and 68% (n=41) were observed for anistreplase compared with 59% (n=85) and 70% (n=43) for IC streptokinase. Of those patients who had coronary artery reperfusion, angiographically demonstrated reocclusion occurred within 24 hours in 3 to 4% of those treated with anistreplase and in 7 to 12% of those treated with streptokinase.

In a multicenter, randomized, comparative study, a patency rate of 72% was obtained with anistreplase compared with 53% for i.v. streptokinase. Patency for 107 patients (54 received anistreplase) was determined by post-treatment angiography.

Anistreplase was also found to have a favorable risk/benefit profile in elderly patients (>65 years, n=940) who participated in clinical trials. Use of anistreplase in patients over 75 years old has not been adequately studied.

Indications And Clinical Uses: For use in the management of AMI in adults for the lysis of thrombi obstructing coronary arteries, the reduction of infarct size, the improvement of ventricular function following AMI, and the reduction of mortality associated with AMI.

Treatment should be initiated as soon as possible after the onset of AMI symptoms.

Contra-Indications: Because thrombolytic therapy increases the risk of bleeding, anistreplase is contraindicated in the following situations: active internal bleeding; history of cerebrovascular accident (CVA); 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 (see Warnings); recent traumatic cardiopulmonary resuscitation; recent severe trauma (see Warnings).

Anistreplase should not be administered to patients having experienced severe allergic reactions to either this product or streptokinase.

Manufacturers’ Warnings In Clinical States: Bleeding (see Adverse Effects): The most common complication associated with anistreplase therapy 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, retroperitoneal, ocular, 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 may contribute to the bleeding. As fibrin is lysed during anistreplase therapy, bleeding from a recent puncture site may occur. Therefore, thrombolytic therapy 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 treatment with anistreplase. Venipunctures should be performed carefully and only as required. Should an arterial puncture be necessary following administration of anistreplase, it is preferable to use an upper-extremity vessel that is accessible to manual compression. A pressure dressing should be applied, and the puncture site should be checked frequently for evidence of bleeding.

Each patient being considered for therapy with anistreplase should be carefully evaluated and anticipated benefits should be weighed against potential risks associated with the therapy. In the following conditions, the risks of anistreplase 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); cerebrovascular disease; recent gastrointestinal or genitourinary bleeding (within 10 days); recent trauma (within 10 days). Hypertension: systolic BP ³180 mm Hg and/or diastolic ³110 mm Hg; high likelihood of left heart thrombus (e.g., mitral stenosis with atrial fibrillation); subacute bacterial endocarditis; hemostatic defects including those secondary to severe hepatic or renal disease; pregnancy; diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site; advanced age (i.e., over 75 years old); 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; acute pericarditis.

Arrhythmias: Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarization, 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 injections of anistreplase are administered (see Adverse Effects).

Hypotension: Hypotension, sometimes severe, not secondary to bleeding or anaphylaxis, has occasionally been observed soon after i.v. anistreplase administration. Often the hypotension is associated with bradycardia. Patients should be monitored closely and, should symptomatic or alarming hypotension occur, appropriate symptomatic treatment should be administered (see Adverse Effects).

Precautions: General: Standard management of myocardial infarction should be implemented concomitantly with anistreplase treatment. Invasive procedures should be minimized (see Warnings). Anaphylactoid reactions have rarely been reported in patients who received anistreplase. Accordingly, adequate treatment provisions such as epinephrine should be available for immediate use (see Adverse Effects). Anistreplase should be administered in a setting where the appropriate personnel and monitoring techniques are readily available.

Readministration: Because of the increased likelihood of resistance due to antistreptokinase antibody, anistreplase may not be effective if administered more than 5 days after prior anistreplase or streptokinase therapy particularly between 5 days and 12 months. Increased antistreptokinase antibody levels after anistreplase or streptokinase may also increase the risk of allergic reactions following readministration.

Repeated administration of anistreplase within 1 week of the initial dose has occurred in 60 patients treated for AMI. The majority of these patients (54/60) received their repeat dosing as part of the early dose-finding studies. Of these, 44 received both doses totaling 30 units of anistreplase or less within 1 hour, 7 received these doses within 24 hours and 3 received these doses between 24 and 72 hours. In addition, there were 6 patients who received a second dose of 30 units of anistreplase. These patients received their second treatment within 24 hours in 4 cases and within 48 hours in the remaining 2 cases.

In the group who received a repeat dose as part of the early dose-ranging studies, there was no evidence that the incidence of any adverse event increased as a consequence of repeat dosing. However, the number of patients in either group was too small to draw definitive conclusions about the safety of readministration within 1 week.

Laboratory Tests: I.V. administration of anistreplase will cause marked decreases in plasminogen and fibrinogen and increases in thrombin time, activated partial thromboplastin, and prothrombin time. Coagulation parameters can be monitored by measurement of thrombin time or prothrombin time. Plasminogen and fibrinogen values have generally returned to normal within 24 to 48 hours of therapy.

Post-dosing coagulation studies are of importance in providing information on which the dose of heparin may be adjusted. Adjustment may be required to maintain the thrombin time or partial thromboplastin time, or similar, at approximately twice the upper limit of laboratory normal range values. These studies may also be of importance in the rare situation in which a patient treated with anistreplase develops severe, uncontrolled bleeding within the first few hours of dosing. In such cases, coagulation monitoring may be helpful in identifying hemostatic deficiencies that may need correction with cryoprecipitate, purified clotting factor concentrates or fresh whole blood. Results of coagulation tests and/or measures of fibrinolytic activity performed during anistreplase therapy may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Anistreplase, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. Collection of blood samples in the presence of aprotinin (2 000 to 3 000 KIU/mL) can, to some extent, mitigate this phenomenon.

Drug Interactions: The use of anistreplase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as ASA and dipyridamole) may increase the risk of bleeding if administered prior to anistreplase therapy.

Use of Anticoagulants: Anistreplase alone or in combination with antiplatelet agents and anticoagulants may cause bleeding complications. Therefore, careful clinical observation is advised, especially at arterial puncture sites.

Heparin anticoagulation has been routinely administered to all patients after dosing with anistreplase. In all but one of the pivotal studies (a comparator study of anistreplase versus heparin), anticoagulant therapy was initiated 4 to 6 hours after anistreplase treatment (approximately when the thrombin time or activated partial thromboplastin time were less than 2 times the upper limit of normal). The use of antiplatelet agents increased the incidence of bleeding events similarly in patients treated with anistreplase or nonthrombolytic therapy. There was no evidence of a synergistic effect of combined anistreplase and antiplatelet agents on bleeding events. In addition, there was no difference in the incidence of hemorrhagic CVAs in anistreplase-treated patients who did or did not receive ASA.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate the carcinogenic potential of the effect on fertility. Studies to determine mutagenicity and chromosomal aberration assays in human lymphocytes were negative in all concentrations tested.

Pregnancy: Animal reproduction studies have not been conducted with anistreplase. It is also not known whether anistreplase can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Anistreplase should be given to a pregnant woman only if clearly needed.

Lactation: It is not known whether anistreplase is excreted in human milk. Because many drugs are excreted in milk, the physician should decide whether the patient should discontinue nursing or not receive anistreplase.

Children: Safety and effectiveness of anistreplase in children have not been established.

Adverse Reactions: Bleeding: The incidence of bleeding (major or minor) varied widely from study to study and may depend on the use of arterial catheterization and other invasive procedures, patient population, and concomitant therapy. The overall incidence of bleeding in patients treated with anistreplase in clinical trials (n=5 275) was 14.6%, with nonpuncture-site bleeding occurring in 10.2% and puncture-site bleeding occurring in 5.7%, of these patients. Bleeding at the puncture site occurred more frequently in clinical trials in which the patients underwent immediate coronary catheterization (13.3%, n=637) compared with those who did not (3.0%, n=2 023). The incidence of presumed intracranial bleeding within 7 days postdosing with anistreplase was 0.57% (n=5 275; 0.34%, etiology confirmed hemorrhagic; 0.23%, etiology not confirmed) compared to 0.16% (n=1 249) after nonthrombolytic therapy.

In the AIMS trial the overall incidence of bleeding in patients treated with anistreplase was 14.8% compared with 3.8% for placebo. The incidence of specific bleeding events were as follows.

In this study there was no difference between anistreplase and placebo in the incidence of major bleeding events. The incidence of intracranial bleeding, cardiac tamponade, a decrease in hemoglobin greater than 50 g/L, or greater than a 15 point decrease in hematocrit, was 1.6% for anistreplase compared with 1.8% for placebo-treated patients.

Should serious bleeding (not controlled by local pressure) occur in a critical location (intracranial, gastrointestinal, retroperitoneal, pericardial), any concomitant heparin should be terminated immediately and the administration of protamine to reverse heparinization should be considered. If necessary, the bleeding tendency can be reversed with appropriate replacement therapy.

Minor bleeding can be anticipated mainly at invaded or disturbed sites. If such bleeding occurs, local measures should be taken to control the bleeding (see Warnings).

Cardiovascular: The most frequently reported adverse experiences in anistreplase trials (n=5 275) were arrhythmia/conduction disorders which were reported in 38% of patients treated with anistreplase and 46% of nonthrombolytic control patients. Hypotension occurred in 10.4% of the 5 275 patients treated with anistreplase compared to 7.9% for patients who received nonthrombolytic treatment (see Warnings).

Allergic-type Reactions: Anaphylactic and anaphylactoid reactions have been observed rarely (0.2%) in patients treated with anistreplase and are similar in incidence to streptokinase. These included symptoms such as bronchospasm or angioedema.

Other milder or delayed effects such as urticaria, itching, flushing, rashes, eosinophilia have been occasionally observed. A delayed purpuric rash appearing 1 to 2 weeks after treatment has been reported in 0.3% of patients. The rash may also be associated with arthralgia, ankle edema, gastrointestinal symptoms, mild hematuria and mild proteinuria. This syndrome was self-limiting and without long-term sequelae.

Risk of Viral Transmission: Six standard production batches of anistreplase (5 different standard production batches of lys-plasminogen) were used in clinical trials designed specifically to monitor possible hepatitis non-A, non-B transmission. No case of hepatitis was diagnosed in the 48 anistreplase-treated patients that qualified for evaluation. Elevated transaminase levels (at least 2.5 times the upper limit of normal) were used as a marker for non-A, non-B hepatitis.

Lys-plasminogen is derived from human plasma obtained from approved sources and tested for absence of viral contamination, including human immunodeficiency virus type-1 (HIV-1) and hepatitis B surface antigen. The manufacturing process includes a vapor-heat treatment step for inactivation of viruses. The entire manufacturing process has also been validated to yield a cumulative reduction of ³10mh221fold HIV-1 infectious particles, i.e., ³10infectious particles removed by vapor-heat treatment and a cumulative total of ³105infectious particles removed by the various steps in the purification process.

Miscellaneous: Since the following experiences may also be associated with AMI or concomitant AMI therapy, the causal relationship to anistreplase administration is unknown.

Cardiovascular: cardiac rupture, chest pain, emboli.

Dermatology: purpura, sweating.

Gastrointestinal: nausea and/or vomiting.

Hemic and Lymphatic: thrombocytopenia.

Metabolic and Nutritional: elevated transaminase levels.

Musculoskeletal: arthralgia.

Nervous: agitation, dizziness, paraesthesia, tremor, vertigo.

Respiratory: dyspnea, lung edema.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no experience with overdosage of anistreplase. Should severe bleeding in a critical location occur, discontinue infusion of anistreplase and any other concomitant anticoagulant therapy immediately. Proteinase inhibitors such as aprotinin (see manufacturer’s prescribing information) may be administered to stop the fibrinolytic action of anistreplase. Attention should also be directed to any hemostatic deficiency (see Adverse Effects). If necessary, blood loss can be managed with whole blood or packed red cells.

Dosage And Administration: Administer anistreplase as soon as possible after the onset of symptoms. Reduction in mortality was observed when anistreplase was administered within 6 hours of onset of AMI symptoms; reperfusion was greatest when anistreplase was administered within 4 hours of symptom onset. Initiation of treatment beyond 6 hours after onset of symptoms has not been adequately studied.

The recommended dose is 30 units of anistreplase administered only by i.v. injection over 2 to 5 minutes into an i.v. line or vein. If anistreplase is administered via an i.v. line, it should only be injected through the injection port attached to the cannula, not added to the infusion bag or injected into the line further up. As long as the dose is administered through the port, there is no need to flush the line.

There are no incompatibilities of anistreplase with the common neutral infusion fluids such as saline and phosphate/saline solutions. Compatibility with 5% glucose has been investigated because of its low pH (4 to 5). This was considered to possibly cause precipitation or dissociation of the anistreplase complex. However, experiments have shown that anistreplase mixtures with 5% glucose do not precipitate. The compatibility of anistreplase with lidocaine or other common antiarrhythmics has not been studied.

Stability and Storage: Anistreplase should be stored in a refrigerator (2 to 8°C) and must not be used after the expiry date printed on the pack and vial. Vials must not be stored at room temperature.

Reconstituted solution should be administered as soon as possible. If unused after 30 minutes the solution must be discarded.

If a vial of anistreplase is removed from the refrigerator but is then not used, the vial can be returned to the refrigerator within 2 to 3 hours, provided the material has not been reconstituted and care has been taken to avoid temperatures greater than 30°C.

Reconstitution: 1. Slowly add 5 mL of Sterile Water for Injection, USP by directing the stream of fluid against the side of the vial. 2. Gently roll the vial, mixing the dry powder and fluid. Do not shake. Try to minimize foaming since it makes it difficult to withdraw product. 3. The reconstituted preparation is a colorless to pale yellow transparent solution. Inspect for particulate matter and discoloration before administration. 4. Withdraw the entire contents of the vial. 5. Do not dilute further, or add to any infusion fluids. 6. Do not add any other medications to the vial or syringe containing anistreplase.

7. If anistreplase is not administered within 30 minutes of reconstitution, it should be discarded.

Availability And Storage: Each unit-dose vial of sterile lyophilized, white to off-white powder contains: anistreplase 30 units, dimethylsulfoxide. Potency is expressed in units of anistreplase using a reference standard which is specific for anistreplase and is not comparable with units used for other fibrinolytics.

EMINASE® Roberts Anistreplase Fibrinolytic Agent

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