TNKASE

Tenecteplase is a tissue plasminogen activator (tPA) produced by recombinant DNA technology using a mammalian cell line (Chinese Hamster Ovary cells). Tenecteplase 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. It has a molecular weight of 58,742 daltons. 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. TNKase (tenecteplase) for injection is a sterile, white to pale yellow, lyophilized powder for intravenous bolus administration after reconstitution with Sterile Water for Injection, USP. Each 25 mg single-dose vial of TNKase nominally contains 25 mg of tenecteplase, arginine (261 mg), phosphoric acid (approximately 80 mg), and polysorbate 20 (2.0 mg). Following reconstitution with the supplied 5.2 mL single-dose vial of Sterile Water for Injection, USP, the final concentration is 5 mg/mL with a pH of approximately 7.3. Each 50 mg single-dose vial of TNKase nominally contains 50 mg of tenecteplase, arginine (522 mg), phosphoric acid (approximately 160 mg), and polysorbate 20 (4.0 mg). Following reconstitution with the supplied 10 mL single-dose vial of Sterile Water for Injection, USP, the final concentration is 5 mg/mL with a pH of approximately 7.3.

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.

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.

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

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

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.

16.2 Storage and Handling Store lyophilized TNKase at room temperature up to 30°C (86°F) or refrigerated at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date stamped on the vial. For storage information for reconstituted TNKase, see Dosage and Administration (2.4) .