Metalyse IV Injection

Metalyse is indicated for use in the reduction of mortality associated with acute myocardial infarction (AMI). Treatment should be initiated as soon as possible after the onset of acute myocardial infarction symptoms.

Metalyse is a tissue plasminogen activator (tPA) produced by recombinant DNA technology using an established mammalian cell line (Chinese Hamster Ovary cells). Metalyse is a 527 amino acid glycoprotein developed by introducing the following modifications to the complementary DNA (cDNA) for natural human tPA: a substitution of threonine 103 with asparagine, and a substitution of asparagine 117 with glutamine, both within the kringle 1 domain, and a tetra-alanine substitution at amino acids 296–299 in the protease domain. Tenectaplase is a sterile, white to off-white, lyophilized powder for single intravenous (IV) bolus administration after reconstitution with Sterile Water for Injection (SWFI), USP. Each vial of Tenectaplase nominally contains 52.5 mg Metalyse, 0.55 g L-arginine, 0.17 g phosphoric acid, and 4.3 mg polysorbate 20, which includes a 5% overfill. Each vial will deliver 50 mg of Metalyse. 

Tenecteplase is a modified form of human tissue plasminogen activator (tPA) that binds to fibrin and converts plasminogen to plasmin. In the presence of fibrin, in vitro studies demonstrate that Tenecteplase conversion of plasminogen to plasmin is increased relative to its conversion in the absence of fibrin. This fibrin specificity decreases systemic activation of plasminogen and the resulting degradation of circulating fibrinogen as compared to a molecule lacking this property. Following administration of 30, 40, or 50 mg of Tenecteplase, there are decreases in circulating fibrinogen (4%-15%) and plasminogen (11%-24%). The clinical significance of fibrinspecificity on safety (e.g., bleeding) or efficacy has not been established. Biological potency is determined by an in vitro clot lysis assay and is expressed in Tenecteplase-specific units. The specific activity of Tenecteplase has been defined as 200 units/mg.

Tenecteplase is for intravenous administration only. The recommended total dose should not exceed 50 mg and is based upon patient weight. A single bolus dose should be administered over 5 seconds based on patient weight. Treatment should be initiated as soon as possible after the onset of AMI symptoms.

• Patient Weight <60 kg: 30 mg Tenecteplase 
• Patient Weight ≥60 to <70 kg: 35 mg Tenecteplase 
• Patient Weight ≥70 to <80 kg: 40 mg Tenecteplase 
• Patient Weight ≥80 to <90 kg: 45 mg Tenecteplase 
• Patient Weight ≥90 kg: 50 mg Tenecteplase

1. The product should be visually inspected prior to administration for particulate matter and discoloration. Tenecteplase may be administered as reconstituted at 5 mg/mL.
2. Precipitation may occur when Tenecteplase is administered in an IV line containing dextrose. Dextrose-containing lines should be flushed with a saline-containing solution prior to and following single bolus administration of Tenecteplase.
3. Reconstituted Tenecteplase should be administered as a single IV bolus over 5 seconds.
4. Because Tenecteplase contains no antibacterial preservatives, it should be reconstituted immediately before use. If the reconstituted Tenecteplase is not used immediately, refrigerate the Tenecteplase vial at 2-8°C and use within 8 hours.
5. Although the supplied syringe is compatible with a conventional needle, this syringe is designed to be used with needleless IV systems. From the information below, follow the instructions applicable to the IV system in use.

Formal interaction studies of Tenectaplase with other drugs have not been performed. Patients studied in clinical trials of Metalyse were routinely treated with heparin and aspirin. Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function. (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after Tenectaplase therapy.

Tenecteplase therapy in patients with acute myocardial infarction is contraindicated in the following situations because of an increased risk of bleeding:

• Active internal bleeding
• History of cerebrovascular accident
• Intracranial or intraspinal surgery or trauma within 2 months
• Intracranial neoplasm, arteriovenous malformation, or aneurysm
• Known bleeding diathesis
• Severe uncontrolled hypertension

The most frequent adverse reaction associated with Metalyse is bleeding. Should serious bleeding occur, concomitant heparin and antiplatelet therapy should be discontinued. Death or permanent disability can occur in patients who experience stroke or serious bleeding episodes. For Metalyse-treated patients in ASSENT-2, the incidence of intracranial hemorrhage was 0.9% and any stroke was 1.8%. The incidence of all strokes, including intracranial bleeding, increases with increasing age

Pregnancy: Tenectaplase has been shown to elicit maternal and embryo toxicity in rabbits given multiple IV administrations. In rabbits administered 0.5, 1.5, and 5.0 mg/kg/day during organogenesis, vaginal hemorrhage resulted in maternal deaths. Subsequent embryonic deaths were secondary to maternal hemorrhage and no fetal anomalies were observed. Tenectaplase does not elicit maternal and embryo toxicity in rabbits following a single IV administration. Thus, in developmental toxicity studies conducted in rabbits, the no observable effect level (NOEL) of a single IV administration of Tenectaplase on maternal or developmental toxicity (5 mg/kg) was approximately 7 times human exposure (based on AUC) at the dose for AMI. There are no adequate and well controlled studies in pregnant women. Tenectaplase should be given to pregnant women only if the potential benefits justify the potential risk to the fetus.

Nursing Mothers: It is not known if Tenectaplase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tenectaplase is administered to a nursing woman.

General: Standard management of myocardial infarction should be implemented concomitantly with Metalyse treatment. Arterial and venous punctures should be minimized. Noncompressible arterial puncture must be avoided and internal jugular and subclavian venous punctures should be avoided to minimize bleeding from the noncompressible sites. In the event of serious bleeding, heparin and antiplatelet agents should be discontinued immediately. Heparin effects can be reversed by protamine.

Readministration: Readministration of plasminogen activators, including Metalyse, to patients who have received prior plasminogen activator therapy has not been systematically studied. Three of 487 patients tested for antibody formation to Metalyse had a positive antibody titer at 30 days. The data reflect the percentage of patients whose test results were considered positive for antibodies to Metalyse in a radioimmunoprecipitation assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Metalyse with the incidence of antibodies to other products may be misleading. Although sustained antibody formation in patients receiving one dose of Metalyse has not been documented, readministration should be undertaken with caution.

Hypersensitivity: Hypersensitivity, including urticarial / anaphylactic reactions, have been reported after administration of Metalyse (e.g., anaphylaxis, angioedema, laryngeal edema, rash, and urticaria). Monitor patients treated with Metalyse during and for several hours after infusion. If symptoms of hypersensitivity occur, appropriate therapy should be initiated.

Pediatric Use: The safety and effectiveness of Metalyse in pediatric patients have not been established.

In elderly patients: The benefits of Metalyse on mortality should be carefully weighed against the risk of increased adverse events, including bleeding.

Fibrinolytics (Thrombolytics)

Store lyophilized Metalyse at controlled room temperature not to exceed 30°C or under refrigeration 2-8°C. Do not use beyond the expiration date stamped on the vial.