ACTIVASE

Alteplase is a tissue plasminogen activator produced by recombinant DNA technology. It is a sterile, purified glycoprotein of 527 amino acids. It is synthesized using the complementary DNA (cDNA) for natural human tissue-type plasminogen activator obtained from a human melanoma cell line. Biological potency is determined by an in vitro clot lysis assay and is expressed in International Units (IU). Activase (alteplase) is a sterile, white to off-white, lyophilized powder for intravenous administration after reconstitution with Sterile Water for Injection, USP. Table 6 Quantitative Composition of the Lyophilized Product 100 mg Vial 50 mg Vial Alteplase 100 mg (58 million IU) 50 mg (29 million IU) L-Arginine 3.5 g 1.7 g Phosphoric Acid 1 g 0.5 g Polysorbate 80 10 mg 5 mg Vacuum No Yes The reconstituted preparation results in a colorless to pale yellow transparent solution containing Activase 1 mg/mL at approximately pH 7.3. The osmolality of this solution is approximately 215 mOsm/kg.

Activase is a tissue plasminogen activator (tPA) indicated for the treatment of: Acute Ischemic Stroke (AIS). ( 1.1 ) Acute Myocardial Infarction (AMI) to reduce mortality and incidence of heart failure. ( 1.2 ) Limitation of Use in AMI: the risk of stroke may be greater than the benefit in patients at low risk of death from cardiac causes. ( 1.2 ) Acute Massive Pulmonary Embolism (PE) for lysis. ( 1.3 ) 1.1 Acute Ischemic Stroke Activase is indicated for the treatment of acute ischemic stroke. Exclude intracranial hemorrhage as the primary cause of stroke signs and symptoms prior to initiation of treatment [see Contraindications (4.1) ] . Initiate treatment as soon as possible but within 3 hours after symptom onset. 1.2 Acute Myocardial Infarction Activase is indicated for use in acute myocardial infarction (AMI) for the reduction of mortality and reduction of the incidence of heart failure. Limitation of Use: The risk of stroke may outweigh the benefit produced by thrombolytic therapy in patients whose AMI puts them at low risk for death or heart failure. 1.3 Pulmonary Embolism Activase is indicated for the lysis of acute massive pulmonary embolism, defined as: Acute pulmonary emboli obstructing blood flow to a lobe or multiple lung segments. Acute pulmonary emboli accompanied by unstable hemodynamics, e.g., failure to maintain blood pressure without supportive measures.

Acute Ischemic Stroke : The recommended dose is 0.9 mg/kg (not to exceed 90 mg total dose) infused intravenously over 60 minutes with 10% of the total dose administered as an initial bolus over 1 minute. ( 2.1 ) Acute Myocardial Infarction : The recommended total dose is based on patient weight, not to exceed 100 mg. ( 2.2 ) Acute Massive Pulmonary Embolism : The recommended dose is 100 mg administered by IV infusion over 2 hours. ( 2.3 ) Do not add other medications to infusions containing Activase. ( 2.5 ) 2.1 Acute Ischemic Stroke Administer Activase as soon as possible but within 3 hours after onset of symptoms. The recommended dose is 0.9 mg/kg (not to exceed 90 mg total dose), with 10% of the total dose administered as an initial intravenous bolus over 1 minute and the remainder infused over 60 minutes. During and following Activase administration for the treatment of acute ischemic stroke, frequently monitor and control blood pressure. In patients without recent use of oral anticoagulants or heparin, Activase treatment can be initiated prior to the availability of coagulation study results. Discontinue Activase if the pretreatment International Normalized Ratio (INR) is greater than 1.7 or the activated partial thromboplastin time (aPTT) is elevated [see Contraindications (4.1) ] . 2.2 Acute Myocardial Infarction Administer Activase as soon as possible after the onset of symptoms. The recommended total doses for acute myocardial infarction (AMI) is based on patient weight, not to exceed 100 mg, regardless of the selected administration regimen (accelerated or 3 hour, described below). There are two Activase dose regimens (accelerated and 3-hour) for use in the management of AMI; there are no controlled studies to compare clinical outcomes with these regimens [see Clinical Studies (14.2) ]. Accelerated Infusion The recommended accelerated infusion dose consists of an IV bolus [see Dosage and Administration (2.4 , 2.5) ] followed by an IV infusion as set forth in Table 1 . Table 1 Accelerated Infusion Weight-Based Doses for Patients with AMI Patient weight Intravenous Bolus First 30 min Next 60 min > 67 kg 15 mg 50 mg 35 mg ≤ 67 kg 15 mg 0.75 mg/kg 0.50 mg/kg The safety and efficacy of accelerated infusion of Activase have only been investigated with concomitant administration of heparin and aspirin [see Clinical Studies (14.2) ] . 3-Hour Infusion For patients weighing ≥ 65 kg, the recommended dose is 100 mg administered as 60 mg in the first hour (6-10 mg administered as a bolus), 20 mg over the second hour, and 20 mg over the third hour. For smaller patients (< 65 kg), a dose of 1.25 mg/kg administered over 3 hours may be used. Weight-based doses are shown in Table 2 . Table 2 3-hour Infusion Weight-Based Doses for Patients with AMI Patient weight Bolus Rest of 1st hour 2nd hour 3rd hour ≥ 65 kg 6-10 mg 50-54 mg 20 mg 20 mg < 65 kg 0.075 mg/kg 0.675 mg/kg 0.25 mg/kg 0.25 mg/kg 2.3 Pulmonary Embolism (PE) The recommended dose is 100 mg administered by IV infusion over 2 hours. Institute parenteral anticoagulation near the end of or immediately following the Activase infusion when the partial thromboplastin time or thrombin time returns to twice normal or less. 2.4 Activase 50 mg Reconstitution and Administration Instructions Activase is for intravenous administration only. Do not add any other medication to infusion solutions containing Activase. Extravasation of Activase infusion can cause ecchymosis or inflammation. If extravasation occurs, terminate the infusion at that intravenous site and apply local therapy. Use within 8 hours following reconstitution (when stored at 2–30°C). Activase contains no antibacterial preservatives. Activase 50 mg Reconstitution Notes Use only the accompanying Sterile Water for Injection (SWFI), USP without preservatives. Do not use Bacteriostatic Water for Injection, USP. Reconstitute using aseptic technique. Slight foaming is not unusual; let stand undisturbed for several minutes to allow large bubbles to dissipate. Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. Activase may be administered as reconstituted at 1 mg/mL or further diluted immediately before administration in an equal volume of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to yield a concentration of 0.5 mg/mL, using either polyvinyl chloride bags or glass vials. Avoid excessive agitation during dilution; mix by gently swirling and/or slow inversion. Activase 50 mg Reconstitution Instructions DO NOT USE IF VACUUM IS NOT PRESENT. Using a large bore needle (e.g., 18 gauge) and a syringe, reconstitute by adding the contents of the accompanying 50 mL vial of SWFI to the 50 mg vial of Activase, directing the SWFI stream into the lyophilized cake. Activase 50 mg Preparation of Bolus Dose Prepare the bolus dose in one of the following ways: Remove the appropriate volume from the vial of reconstituted (1 mg/mL) Activase using a syringe and needle. The syringe should not be primed with air and the needle should be inserted into the Activase vial stopper. Remove the appropriate volume from a port (second injection site) on the infusion line after the infusion set is primed. Program an infusion pump to deliver the appropriate volume as a bolus at the initiation of the infusion. Activase 50 mg Administration Following bolus dose, if indicated [see Dosage and Administration (2.1 , 2.2) ]: Administer using either a polyvinyl chloride bag or glass vial and infusion set. 2.5 Activase 100 mg Instructions for Use See the enclosed Instructions for Use for Activase 100 mg enclosed in the carton for reconstitution and administration instructions. Alternative Dilution Instructions Activase may be administered as reconstituted at 1 mg/mL or further diluted immediately before administration in an equal volume of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to yield a concentration of 0.5 mg/mL, using either polyvinyl chloride bags or glass vials.

General Active internal bleeding. ( 4.1 , 4.2 ) Recent intracranial or intraspinal surgery or serious head trauma. ( 4.1 , 4.2 ) Intracranial conditions that may increase the risk of bleeding. ( 4.1 , 4.2 ) Bleeding diathesis. ( 4.1 , 4.2 ) Current severe uncontrolled hypertension. ( 4.1 , 4.2 ) Acute Ischemic Stroke Current intracranial hemorrhage. ( 4.1 ) Subarachnoid hemorrhage. ( 4.1 ) Acute Myocardial Infarction or Pulmonary Embolism History of recent stroke. ( 4.2 ) 4.1 Acute Ischemic Stroke Do not administer Activase to treat acute ischemic stroke in the following situations in which the risk of bleeding is greater than the potential benefit [see Warnings and Precautions (5.1) ] : Current intracranial hemorrhage Subarachnoid hemorrhage Active internal bleeding Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma Presence of intracranial conditions that may increase the risk of bleeding (e.g., some neoplasms, arteriovenous malformations, or aneurysms) Bleeding diathesis Current severe uncontrolled hypertension. 4.2 Acute Myocardial Infarction or Pulmonary Embolism Do not administer Activase for treatment of AMI or PE in the following situations in which the risk of bleeding is greater than the potential benefit [see Warnings and Precautions (5.1) ]: Active internal bleeding History of recent stroke Recent (within 3 months) intracranial or intraspinal surgery or serious head trauma Presence of intracranial conditions that may increase the risk of bleeding (e.g. some neoplasms, arteriovenous malformations, or aneurysms) Bleeding diathesis Current severe uncontrolled hypertension.

The following adverse reactions are discussed in greater detail in the 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) ] The most frequently occurring adverse reaction ( > 5%) 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 clinical practice. The most frequent adverse reaction associated with Activase in all approved indications is bleeding. Bleeding Acute Ischemic Stroke (AIS) In clinical studies in patients with AIS (Studies 1 and 2) the incidence of intracranial hemorrhage, especially symptomatic intracranial hemorrhage, was higher in Activase-treated patients than in placebo patients. A dose-finding study of Activase suggested that doses greater than 0.9 mg/kg may be associated with an increased incidence of intracranial hemorrhage. The incidence of all-cause 90-day mortality, intracranial hemorrhage, and new ischemic stroke following Activase treatment compared to placebo are presented in Table 3 as a combined safety analysis (n=624) for Studies 1 and 2. These data indicate a significant increase in intracranial hemorrhage following Activase treatment, particularly symptomatic intracranial hemorrhage within 36 hours. There was no increase in the incidences of 90-day mortality or severe disability in Activase-treated patients compared to placebo. Table 3 Combined Safety Outcomes for Studies 1 and 2 Placebo (n= 312) Activase (n=312) p-Value Fisher's Exact Test. All-Cause 90-day Mortality 64 (20.5%) 54 (17.3%) 0.36 Total ICH Within trial follow-up period. Symptomatic intracranial hemorrhage was defined as the occurrence of sudden clinical worsening followed by subsequent verification of intracranial hemorrhage on CT scan. Asymptomatic intracranial hemorrhage was defined as intracranial hemorrhage detected on a routine repeat CT scan without preceding clinical worsening. 20 (6.4%) 48 (15.4%) <0.01 Symptomatic 4 (1.3%) 25 (8.0%) <0.01 Asymptomatic 16 (5.1%) 23 (7.4%) 0.32 Symptomatic Intracranial Hemorrhage within 36 hours 2 (0.6%) 20 (6.4%) <0.01 New Ischemic Stroke (3-months) 17 (5.4%) 18 (5.8%) 1.00 Bleeding events other than intracranial hemorrhage were noted in the studies of AIS and were consistent with the general safety profile of Activase. In Studies 1 and 2, the frequency of bleeding requiring red blood cell transfusions was 6.4% for Activase-treated patients compared to 3.8% for placebo (p = 0.19). Although exploratory analyses of Studies 1 and 2 suggest that severe neurological deficit (National Institutes of Health Stroke Scale [NIHSS > 22]) at presentation was associated with an increased risk of intracranial hemorrhage, efficacy results suggest a reduced but still favorable clinical outcome for these patients. Acute Myocardial Infarction (AMI) For the 3-hour infusion regimen in the treatment of AMI, the incidence of significant internal bleeding (estimated as > 250 mL blood loss) has been reported in studies in over 800 patients ( Table 4 ). These data do not include patients treated with the Activase accelerated infusion. Table 4 Incidence of Bleeding in 3-Hour Infusion in AMI Patients Total Dose ≤100 mg Gastrointestinal 5% Genitourinary 4% Ecchymosis 1% Retroperitoneal <1% Epistaxis <1% Gingival <1% The incidence of intracranial hemorrhage in AMI patients treated with Activase is presented in Table 5 . Table 5 Incidence of Intracranial Hemorrhage in AMI Patients Dose Number of Patients Intracranial Hemorrhage (%) 100 mg, 3-hour 3272 0.4 ≤ 100 mg, accelerated 10,396 0.7 150 mg 1779 1.3 1-1.4 mg/kg 237 0.4 A dose of 150 mg or greater should not be used in the treatment of AMI because it has been associated with an increase in intracranial bleeding. Pulmonary Embolism (PE) For acute massive pulmonary embolism, bleeding events were consistent with the general safety profile observed with Activase treatment of AMI patients receiving the 3-hour infusion regimen. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of Activase. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions are frequent sequelae of the underlying disease, and the effect of Activase on the incidence of these events is unknown. Acute Ischemic Stroke: Cerebral edema, cerebral herniation, seizure, new ischemic stroke, embolism. These events may be life threatening and may lead to death. Acute Myocardial Infarction: Arrhythmias, AV block, cardiogenic shock, heart failure, cardiac arrest, recurrent ischemia, myocardial reinfarction, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, thromboembolism, pulmonary edema. These events may be life threatening and may lead to death. Nausea and/or vomiting, hypotension and fever have also been reported. Pulmonary Embolism: Pulmonary reembolization, pulmonary edema, pleural effusion, thromboembolism, hypotension. These events may be life threatening and may lead to death. Fever has also been reported.

The interaction of Activase with other cardioactive or cerebroactive drugs has not been studied. Anticoagulants and antiplatelet drugs increase the risk of bleeding if administered prior to, during, or after Activase therapy. In the post-marketing setting, there have been reports of angioedema in patients (primarily patients with AIS) receiving concomitant angiotensin-converting enzyme inhibitors. [see Warnings and Precautions (5.2) ]. Anticoagulants and drugs that inhibit platelet function increase the risk of bleeding when administered with Activase therapy. ( 7 ) Concomitant angiotensin-converting enzyme inhibitors may increase the risk of angioedema. ( 7 )

16.2 Stability and Storage Store lyophilized Activase at controlled room temperature not to exceed 30°C (86°F), or under refrigeration at 2° to 8°C (36° to 46°F). Protect the lyophilized material during extended storage from excessive exposure to light. If stored between 2-30°C (36-86°F), Activase may be used within 8 hours following reconstitution. Discard any unused solution after administration is complete. Do not use beyond the expiration date stamped on the vial.