TNKase

1 INDICATIONS AND USAGE TNKase is a tissue plasminogen activator (tPA) indicated: for the treatment of acute ischemic stroke (AIS) in adults. ( 1.1 ) to reduce the risk of death associated with acute ST elevation myocardial infarction (STEMI) in adults. ( 1.2 ) 1.1 Acute Ischemic Stroke TNKase is indicated for the treatment of acute ischemic stroke (AIS) in adults. 1.2 Acute ST Elevation Myocardial Infarction TNKase is indicated to reduce the risk of death associated with acute ST elevation myocardial infarction (STEMI) in adults.

2 DOSAGE AND ADMINISTRATION TNKase is for intravenous administration only, administered as a single bolus over 5 seconds. ( 2.1 , 2.2 ) AIS Initiate treatment as soon as possible and within 3 hours after the onset of stroke symptoms. ( 2.1 ) Individualize dosage based on patient's weight; the maximum recommended dose is 25 mg (5 mL). ( 2.1 ) Acute STEMI Initiate treatment as soon as possible after the onset of STEMI symptoms. ( 2.2 ) Individualize dosage based on patient's weight; the maximum recommended dose is 50 mg (10 mL). ( 2.2 ) 2.1 Recommended Dosage for Acute Ischemic Stroke Initiate treatment as soon as possible and within 3 hours after the onset of stroke symptoms. TNKase is for intravenous (IV) administration only, administered as a single bolus over 5 seconds. Individualize dosage based on the patient's weight (see Table 1 ). The maximum recommended dose is 25 mg (5 mL). Table 1 Recommended Dosage for Acute Ischemic Stroke Patient Weight (kg) TNKase (mg) Volume TNKase to be administered (mL) less than 60 kg 15 mg 3 mL 60 kg to less than 70 kg 17.5 mg 3.5 mL 70 kg to less than 80 kg 20 mg 4 mL 80 kg to less than 90 kg 22.5 mg 4.5 mL 90 kg or more 25 mg 5 mL During and following TNKase administration for the treatment of acute ischemic stroke, frequently monitor and control blood pressure. In patients without recent use of oral anticoagulants or heparin, TNKase treatment can be initiated prior to the availability of coagulation study results. If the pretreatment International Normalized Ratio (INR) is greater than 1.7 or the activated partial thromboplastin time (aPTT) is elevated, closely monitor patients [see Contraindications (4) ]. 2.2 Recommended Dosage for Acute ST Elevation Myocardial Infarction Initiate treatment as soon as possible after the onset of STEMI symptoms. TNKase is for intravenous (IV) administration only, administered as a single bolus over 5 seconds. Individualize dosage based on the patient's weight (see Table 2 ). The maximum recommended dose is 50 mg (10 mL). Table 2 Recommended Dosage for Acute ST Elevation Myocardial Infarction Patient Weight (kg) TNKase (mg) Volume TNKase to be administered (mL) less than 60 kg 30 mg 6 mL 60 kg to less than 70 kg 35 mg 7 mL 70 kg to less than 80 kg 40 mg 8 mL 80 kg to less than 90 kg 45 mg 9 mL 90 kg or more 50 mg 10 mL 2.3 Preparation Follow the steps below to prepare TNKase for administration: Only use the supplied Sterile Water for Injection diluent vial for reconstitution as shown below. TNKase Vial Strength Sterile Water for Injection Vial Volume 25 mg 5.2 mL 50 mg 10 mL Using a sterile syringe, aseptically withdraw the Sterile Water for Injection from the diluent vial and reconstitute the TNKase vial by directing the stream into the lyophilized powder to obtain a final concentration of 5 mg/mL. Slight foaming upon reconstitution is not unusual; any large bubbles will dissipate if the product is allowed to stand undisturbed for several minutes. Gently swirl until contents are completely dissolved. DO NOT SHAKE. The reconstituted preparation results in a colorless to pale yellow transparent solution. Determine the appropriate dose of TNKase [see Dosage and Administration (2.1 , 2.2) ] and withdraw the required volume (in milliliters) from the reconstituted vial into the syringe. Discard any unused solution. 2.4 Administration Follow the steps below for administration of TNKase: Visually inspect the reconstituted product in the syringe for particulate matter and discoloration prior to administration. Precipitation may occur when TNKase is administered in an intravenous line containing dextrose. Flush dextrose-containing lines with 0.9% Sodium Chloride Injection solution prior to and following single bolus administration of TNKase. Using sterile technique, connect the syringe directly to the intravenous port. Administer reconstituted TNKase as a single intravenous bolus over 5 seconds. Because TNKase contains no antibacterial preservatives, reconstitute immediately before use. If the reconstituted TNKase is not used immediately, refrigerate the TNKase vial at 2°C to 8°C (36°F to 46°F) and use within 8 hours. Dispose of the syringe per established procedures. 2.5 Chemical Incompatibilities TNKase is incompatible with dextrose containing solutions. When used together, precipitation may occur. Flush dextrose containing lines with 0.9% Sodium Chloride Injection solution before using TNKase.

4 CONTRAINDICATIONS AIS and STEMI Active internal bleeding ( 4 ) Intracranial or intraspinal surgery or trauma within 2 months ( 4 ) Known bleeding diathesis ( 4 ) Current severe uncontrolled hypertension ( 4 ) Presence of intracranial conditions that may increase the risk of bleeding (e.g., intracranial neoplasm, arteriovenous malformation, or aneurysm) ( 4 ) AIS Active intracranial hemorrhage ( 4 ) Acute STEMI History of intracranial hemorrhage History of ischemic stroke within 3 months ( 4 ) AIS and Acute STEMI TNKase is contraindicated in any patients with: Active internal bleeding Intracranial or intraspinal surgery or trauma within 2 months Known bleeding diathesis Current severe uncontrolled hypertension Presence of intracranial conditions that may increase the risk of bleeding (e.g., intracranial neoplasm, arteriovenous malformation, or aneurysm) AIS TNKase is also contraindicated in patients for the treatment of AIS with: Active intracranial hemorrhage Acute STEMI TNKase is also contraindicated in patients for the treatment of STEMI with: History of intracranial hemorrhage History of ischemic stroke within 3 months

5 WARNINGS AND PRECAUTIONS Bleeding: Increases the risk of bleeding. Avoid intramuscular injections. Monitor for bleeding. ( 5.1 ) Hypersensitivity: Monitor patients treated with TNKase during and for several hours after administration. If symptoms of hypersensitivity occur, initiate appropriate therapy (e.g., antihistamines, corticosteroids, epinephrine). ( 5.2 ) Thromboembolism: The use of thrombolytics can increase the risk of thrombo-embolic events in patients with high likelihood of left heart thrombus. ( 5.3 ) Cholesterol Embolization: Has been reported in patients treated with thrombolytic agents. ( 5.4 ) Arrhythmias: It is recommended that anti-arrhythmic therapy for bradycardia and/or ventricular irritability be available when TNKase is administered. ( 5.5 ) Increased Risk of Heart Failure and Recurrent Ischemia when used with Planned Percutaneous Coronary Intervention in STEMI: In patients with a large ST segment elevation myocardial infarction, choose either thrombolysis or PCI as the primary treatment for reperfusion. Rescue PCI or subsequent elective PCI may be performed after administration of thrombolytic therapies if medically appropriate. ( 5.6 ) 5.1 Bleeding TNKase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. Avoid intramuscular injections and trauma to the patient while on TNKase. Perform arterial and venous punctures carefully and only as required. To minimize bleeding from noncompressible sites, avoid internal jugular and subclavian venous punctures. If an arterial puncture is necessary during TNKase administration, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. Should serious bleeding that is not controlled by local pressure occur, discontinue any concomitant heparin or antiplatelet agents immediately and treat appropriately. Because of the higher risk of intracranial hemorrhage in patients treated for acute ischemic stroke, limit treatment to facilities that can provide timely access to appropriate evaluation and management of intracranial hemorrhage. Aspirin and heparin have been administered concomitantly with and following administration of TNKase in the management of acute myocardial infarction, but the concomitant administration of heparin and aspirin with and following administration of TNKase for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or TNKase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of TNKase, while patients are still receiving anticoagulant therapy. If serious bleeding occurs, treat appropriately. In the following conditions, the risks of bleeding with TNKase therapy for all approved indications are increased and should be weighed against the anticipated benefits: Recent major surgery or procedure (e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels) Cerebrovascular disease Recent intracranial hemorrhage (if not contraindicated) Recent gastrointestinal or genitourinary bleeding Recent trauma Hypertension: systolic BP above 175 mm Hg or diastolic BP above 110 mm Hg Acute pericarditis Subacute bacterial endocarditis Hemostatic defects including those secondary to severe hepatic or renal disease Significant hepatic dysfunction Pregnancy Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions Septic thrombophlebitis or occluded AV cannula at seriously infected site Advanced age [see Use in Specific Populations (8.5) ] Patients currently receiving 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. 5.2 Hypersensitivity Hypersensitivity, including urticarial / anaphylactic reactions, have been reported after administration of TNKase (e.g., anaphylaxis, angioedema, laryngeal edema, rash, and urticaria). Monitor patients treated with TNKase during and for several hours after administration. If symptoms of hypersensitivity occur, initiate appropriate therapy (e.g., antihistamines, corticosteroids, epinephrine). 5.3 Thromboembolism The use of thrombolytics can increase the risk of thrombo-embolic events in patients with high likelihood of left heart thrombus, such as patients with mitral stenosis or atrial fibrillation. 5.4 Cholesterol Embolization Cholesterol embolism has been reported in patients treated with thrombolytic agents. Investigate cause of any new embolic event and treat appropriately. 5.5 Arrhythmias Coronary thrombolysis may result in arrhythmias associated with reperfusion. These arrhythmias (such as sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, ventricular tachycardia) 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 is administered. 5.6 Increased Risk of Heart Failure and Recurrent Ischemia when used with Planned Percutaneous Coronary Intervention (PCI) in STEMI In a trial of patients with STEMI, there were worse outcomes in the individual components of the primary endpoint between TNKase plus PCI versus PCI alone (mortality 6.7% vs. 4.9%, respectively; cardiogenic shock 6.3% vs. 4.8%, respectively; and CHF 12% vs. 9.2%, respectively). In addition, there were worse outcomes in recurrent MI (6.1% vs. 3.7%, respectively; p = 0.03) and repeat target vessel revascularization (6.6% vs. 3.4%, respectively; p = 0.0045) in patients receiving TNKase plus PCI versus PCI alone [see Clinical Studies (14.2) ] . 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.

7 DRUG INTERACTIONS During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. ( 7.1 ) 7.1 Drug/Laboratory Test Interactions During TNKase 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in other sections of the label: Bleeding [see Contraindications (4) , Warnings and Precautions (5.1) ] Hypersensitivity [see Warnings and Precautions (5.2) ] Thromboembolism [see Warnings and Precautions (5.3) ] Cholesterol Embolization [see Warnings and Precautions (5.4) ] Arrhythmias [see Warnings and Precautions (5.5) ] Increased Risk of Heart Failure and Recurrent Ischemia when used with Planned Percutaneous Coronary Intervention (PCI) in STEMI [see Warnings and Precautions (5.6) ] The most common adverse reaction is bleeding. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequent adverse reaction associated with TNKase in all approved indications is bleeding. Acute Ischemic Stroke In Trial 1, the safety of TNKase for the treatment of acute ischemic stroke (AIS) was evaluated in 592 patients who received TNKase at the recommended dosage within 0 to 3 hours of the onset of stroke symptoms (Alteplase compared to Tenecteplase (AcT); Trial 1) [see Dosage and Administration (2.1) and Clinical Studies (14.1) ] . Table 3 describes the incidence of adverse reactions in patients with AIS in Trial 1. Table 3 Incidence of Adverse Reactions in Trial 1 in Patients Treated for Acute Ischemic Stroke Within 0 to 3 Hours from Symptom Onset Adverse Reaction TNKase N=592 % Activase N= 555 % Death 15.0 15.0 Symptomatic intracerebral hemorrhage intracerebral hemorrhage that, in the opinion of the investigator, was temporally related to and directly responsible for worsening of the neurological condition 3.4 3.1 Extracranial (peripheral) bleeding requiring blood transfusion 1.0 0.7 Orolingual angioedema 1.0 1.4

8.1 Pregnancy Risk Summary There are risks to the mother and fetus from acute ST elevation myocardial infarction and acute ischemic stroke, which are medical emergencies in pregnancy and can be fatal if left untreated (see Clinical Considerations ). Published data consisting of a small number of case reports involving the use of related thrombolytic agents in pregnant women have not identified an increased risk of major birth defects. There are no data on the use of tenecteplase during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. TNKase does not elicit maternal and direct embryo toxicity in rabbits following a single IV administration. In developmental toxicity studies conducted in rabbits, the no observable effect level (NOEL) of a single IV administration of TNKase on maternal or developmental toxicity (5 mg/kg) was approximately 7 times human exposure (based on AUC) at the dose for STEMI. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Acute ST elevation myocardial infarction and acute ischemic stroke are medical emergencies which can be fatal if left untreated. Life-sustaining therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of tenecteplase on the fetus.