TNKase

TNKase® (Tenecteplase) is supplied as a sterile, lyophilized powder in a 50 mg vial under partial vacuum. Each 50 mg vial of TNKase (tenecteplase) is packaged with one 10 mL vial of Sterile Water for Injection,USP for reconstitution,the B-D® 10 mL syringe with TwinPak™ Dual Cannula Device, and three alcohol prep pads.NDC 50242-038-61.

Stability and Storage

Store lyophilized TNKase (tenecteplase) at controlled room temperature not to exceed 30°C (86°F) or under refrigeration 2–8°C (36–46°F). Do not use beyond the expiration date stamped on the vial.

Manufactured by: Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080-4990. Code revision January 2008. FDA approval June 2000. FDA Rev date: 6/2/2000

TNKase® (Tenecteplase) 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 AMI symptoms (see Clinical Studies).

Dosage

TNKase® (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 (see Clinical Studies).

Dose Information Table

The safety and efficacy of TNKase (tenecteplase) have only been investigated with concomitant administration of heparin and aspirin as described in Clinical Studies.

THE 10 mL SYRINGE WITH TWINPAK™ DUAL CANNULA DEVICE

Reconstitution

NOTE: Read all instructions completely before beginning reconstitution and administration.

1. Remove the shield assembly from the supplied B-D® 10 mL syringe with TwinPak™ Dual Cannula Device (see figure) and aseptically withdraw 10 mL of Sterile Water for Injection (SWFI), USP, from the supplied diluent vial using the red hub cannula syringe filling device. Do not use Bacteriostatic Water for Injection, USP.
   Note: Do not discard the shield assembly.
2. Inject the entire contents of the syringe (10 mL) into the TNKase (tenecteplase) vial directing the diluent stream into the powder. Slight foaming upon reconstitution is not unusual; any large bubbles will dissipate if the product is allowed to stand undisturbed for several minutes.
3. Gently swirl until contents are completely dissolved. DO NOT SHAKE. The reconstituted preparation results in a colorless to pale yellow transparent solution containing TNKase (tenecteplase) at 5 mg/mL at a pH of approximately 7.3. The osmolality of this solution is approximately 290 mOsm/kg.
4. Determine the appropriate dose of TNKase (tenecteplase) (see Dose Information Table) and withdraw this volume (in milliliters) from the reconstituted vial with the syringe. Any unused solution should be discarded.
5. Once the appropriate dose of TNKase (tenecteplase) is drawn into the syringe, stand the shield vertically on a flat surface (with green side down) and passively recap the red hub cannula.
6. Remove the entire shield assembly, including the red hub cannula, by twisting counterclockwise. Note: The shield assembly also contains the clear-ended blunt plastic cannula; retain for split septum IV access.

Administration

1. The product should be visually inspected prior to administration for particulate matter and discoloration. TNKase (tenecteplase) may be administered as reconstituted at 5 mg/mL.
2. Precipitation may occur when TNKase (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 TNKase (tenecteplase).
3. Reconstituted TNKase (tenecteplase) should be administered as a single IV bolus over 5 seconds.
4. Because TNKase (tenecteplase) contains no antibacterial preservatives, it should be reconstituted immediately before use. If the reconstituted TNKase (tenecteplase) is not used immediately, refrigerate the TNKase (tenecteplase) vial at 2–8°C (36–46°F) 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.
   Split septum IV system:
   • Remove the green cap.
   • Attach the clear-ended blunt plastic cannula to the syringe.
   • Remove the shield and use the blunt plastic cannula to access the split septum injection port.
   • Because the blunt plastic cannula has two side ports, air or fluid expelled through the cannula will exit in two sideways directions; direct away from face or mucous membranes.
   
   Luer-Lok® system: Connect syringe directly to IV port.
   Conventional needle (not supplied in this kit): Attach a large bore needle, e.g.,18 gauge, to the syringe's universal Luer-Lok®.
6. Dispose of the syringe, cannula and shield per established procedures.

TNKase (tenecteplase) therapy in patients with acute myocardial infarction is contraindicated in the following situations because of an increased risk of bleeding (see WARNINGS):

• 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

WARNINGS

Bleeding

The most common complication encountered during TNKase (tenecteplase) therapy is bleeding. The type of bleeding associated with thrombolytic therapy can be divided into two broad categories:

• Internal bleeding, involving intracranial and retroperitoneal sites, or the gastrointestinal,genitourinary, or respiratory tracts.
• Superficial or surface bleeding,observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or sites of recent surgical intervention.

Should serious bleeding (not controlled by local pressure) occur, any concomitant heparin or antiplatelet agents should be discontinued immediately.

In clinical studies of TNKase (tenecteplase) , patients were treated with both aspirin and heparin. Heparin may contribute to the bleeding risks associated with TNKase (tenecteplase). The safety of the use of TNKase (tenecteplase) with other antiplatelet agents has not been adequately studied (see PRECAUTIONS: DRUG INTERACTIONS). Intramuscular injections and nonessential handling of the patient should be avoided for the first few hours following treatment with TNKase (tenecteplase). Venipunctures should be performed and monitored carefully.

Should an arterial puncture be necessary during the first few hours following TNKase (tenecteplase) therapy, 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.

Each patient being considered for therapy with TNKase (tenecteplase) should be carefully evaluated and anticipated benefits weighed against potential risks associated with therapy. In the following conditions, the risk of TNKase (tenecteplase) therapy may be increased and should be weighed against the anticipated benefits:

• Recent major surgery,e.g.,coronary artery bypass graft,obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels
• Cerebrovascular disease
• Recent gastrointestinal or genitourinary bleeding
• Recent trauma
• Hypertension: systolic BP ≥ 180 mm Hg and/or diastolic BP ≥ 110 mm Hg
• High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
• Acute pericarditis
• Subacute bacterial endocarditis
• Hemostatic defects, including those secondary to severe hepatic or renal disease
• Severe hepatic dysfunction
• Pregnancy
• Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions
• Septic thrombophlebitis or occluded AV cannula at seriously infected site
• Advanced age (see PRECAUTIONS: Geriatric Use)
• Patients currently receiving oral anticoagulants,e.g., warfarin sodium
• Recent administration of GP IIb/IIIa inhibitors
• Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location

Cholesterol Embolization

Cholesterol embolism 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 may 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 acute myocardial infarction and may be managed with standard anti-arrhythmic measures.It is recommended that anti-arrhythmic therapy for bradycardia and/or ventricular irritability be available when TNKase (tenecteplase) is administered.

Use with Percutaneous Coronary Intervention (PCI)

In patients with large ST segment elevation myocardial infarction, physicians should choose either thrombolysis or PCI as the primary treatment strategy for reperfusion.Rescue PCI or subsequent elective PCI may be performed after administration of thrombolytic therapies if medically appropriate; however,the optimal use of adjunctive antithrombotic and antiplatelet therapies in this setting is unknown.

PRECAUTIONS

General

Standard management of myocardial infarction should be implemented concomitantly with TNKase (tenecteplase) 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 TNKase (tenecteplase) , to patients who have received prior plasminogen activator therapy has not been systematically studied.Three of 487 patients tested for antibody formation to TNKase (tenecteplase) had a positive antibody titer at 30 days. The data reflect the percentage of patients whose test results were considered positive for antibodies to TNKase (tenecteplase) 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 TNKase (tenecteplase) with the incidence of antibodies to other products may be misleading. Although sustained antibody formation in patients receiving one dose of TNKase (tenecteplase) has not been documented, readministration should be undertaken with caution. If an anaphylactic reaction occurs, appropriate therapy should be administered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals have not been performed to evaluate the carcinogenic potential, mutagenicity, or the effect on fertility.

Pregnancy (Category C)

TNKase (tenecteplase) 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, vaginal hemorrhage resulted in maternal deaths. Subsequent embryonic deaths were secondary to maternal hemorrhage and no fetal anomalies were observed. TNKase (tenecteplase) 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 TNKase (tenecteplase) on maternal or developmental toxicity was 5 mg/kg (approximately 8–10 times the human dose). There are no adequate and well-controlled studies in pregnant women.TNKase (tenecteplase) 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 TNKase (tenecteplase) is excreted in human milk.Because many drugs are excreted in human milk, caution should be exercised when TNKase (tenecteplase) is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of TNKase (tenecteplase) in pediatric patients have not been established.

Geriatric Use

Of the patients in ASSENT-2 who received TNKase (tenecteplase) , 4,958 (59%) were under the age of 65; 2,256 (27%) were between the ages of 65 and 74; and 1,244 (15%) were 75 and over. The 30-day mortality rates by age were 2.5% in patients under the age of 65, 8.5% in patients between the ages of 65 and 74, and 16.2% in patients age 75 and over. The ICH rates were 0.4% in patients under the age of 65, 1.6% in patients between the ages of 65 and 74,and 1.7% in patients age 75 and over.The rates of any stroke were 1.0% in patients under the age of 65,2.9% in patients between the ages of 65 and 74,and 3.0% in patients age 75 and over.Major bleeding rates,defined as bleeding requiring blood transfusion or leading to hemodynamic compromise, were 3.1% in patients under the age of 65,6.4% in patients between the ages of 65 and 74,and 7.7% in patients age 75 and over.In elderly patients,the benefits of TNKase (tenecteplase) on mortality should be carefully weighed against the risk of increased adverse events,including bleeding.

SIDE EFFECTS

Bleeding

The most frequent adverse reaction associated with TNKase is bleeding (see WARNINGS).

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 TNKase (tenecteplase) -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 (see PRECAUTIONS: Geriatric Use).

In the ASSENT-2 study, the following bleeding events were reported (see Table 3).

Table 3: ASSENT-2
Non-ICH Bleeding Events

Non-intracranial major bleeding and the need for blood transfusions were lower in patients treated with TNKase (tenecteplase).

Types of major bleeding reported in 1% or more of the patients were hematoma (1.7%) and gastrointestinal tract (1%). Types of major bleeding reported in less than 1% of the patients were urinary tract, puncture site (including cardiac catheterization site), retroperitoneal, respiratory tract,and unspecified. Types of minor bleeding reported in 1% or more of the patients were hematoma (12.3%), urinary tract (3.7%), puncture site (including cardiac catheterization site) (3.6%), pharyngeal (3.1%), gastrointestinal tract (1.9%), epistaxis (1.5%),and unspecified (1.3%).

Allergic Reactions

Allergic-type reactions (e.g., anaphylaxis, angioedema, laryngeal edema,rash, and urticaria) have rarely ( < 1%) been reported in patients treated with TNKase (tenecteplase).Anaphylaxis was reported in < 0.1% of patients treated with TNKase (tenecteplase) ; however, causality was not established. When such reactions occur, they usually respond to conventional therapy.

Other Adverse Reactions

The following adverse reactions have been reported among patients receiving TNKase (tenecteplase) in clinical trials. These reactions are frequent sequelae of the underlying disease, and the effect of TNKase (tenecteplase) on the incidence of these events is unknown.

These events include cardiogenic shock, arrhythmias, atrioventricular block, pulmonary edema, heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial reinfarction, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, thrombosis, embolism, and electromechanical dissociation. These events can be life-threatening and may lead to death. Nausea and/or vomiting, hypotension,and fever have also been reported.

DRUG INTERACTIONS

Formal interaction studies of TNKase (tenecteplase) with other drugs have not been performed. Patients studied in clinical trials of TNKase (tenecteplase) 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 TNKase (tenecteplase) therapy.

Drug/Laboratory Test Interactions

During TNKase (tenecteplase) therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, 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.

Bleeding

The most frequent adverse reaction associated with TNKase is bleeding (see WARNINGS).

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 TNKase (tenecteplase) -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 (see PRECAUTIONS: Geriatric Use).

In the ASSENT-2 study, the following bleeding events were reported (see Table 3).

Table 3: ASSENT-2
Non-ICH Bleeding Events

Non-intracranial major bleeding and the need for blood transfusions were lower in patients treated with TNKase (tenecteplase).

Types of major bleeding reported in 1% or more of the patients were hematoma (1.7%) and gastrointestinal tract (1%). Types of major bleeding reported in less than 1% of the patients were urinary tract, puncture site (including cardiac catheterization site), retroperitoneal, respiratory tract,and unspecified. Types of minor bleeding reported in 1% or more of the patients were hematoma (12.3%), urinary tract (3.7%), puncture site (including cardiac catheterization site) (3.6%), pharyngeal (3.1%), gastrointestinal tract (1.9%), epistaxis (1.5%),and unspecified (1.3%).

Allergic Reactions

Allergic-type reactions (e.g., anaphylaxis, angioedema, laryngeal edema,rash, and urticaria) have rarely ( < 1%) been reported in patients treated with TNKase (tenecteplase).Anaphylaxis was reported in < 0.1% of patients treated with TNKase (tenecteplase) ; however, causality was not established. When such reactions occur, they usually respond to conventional therapy.

Other Adverse Reactions

The following adverse reactions have been reported among patients receiving TNKase (tenecteplase) in clinical trials. These reactions are frequent sequelae of the underlying disease, and the effect of TNKase (tenecteplase) on the incidence of these events is unknown.

These events include cardiogenic shock, arrhythmias, atrioventricular block, pulmonary edema, heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial reinfarction, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, thrombosis, embolism, and electromechanical dissociation. These events can be life-threatening and may lead to death. Nausea and/or vomiting, hypotension,and fever have also been reported.

No information provided.

In patients with acute myocardial infarction (AMI), TNKase (tenecteplase) administered as a single bolus exhibits a biphasic disposition from the plasma. Tenecteplase was cleared from the plasma with an initial half-life of 20 to 24 minutes. The terminal phase half-life of Tenecteplase was 90 to 130 minutes. In 99 of 104 patients treated with Tenecteplase, mean plasma clearance ranged from 99 to 119 mL/min.

The initial volume of distribution is weight related and approximates plasma volume. Liver metabolism is the major clearance mechanism for Tenecteplase.