Activase

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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…

5 WARNINGS AND PRECAUTIONS Increases the risk of bleeding. Avoid intramuscular injections. Monitor for bleeding. If serious bleeding occurs, discontinue Activase. ( 5.1 ) Monitor patients during and for several hours after infusion for hypersensitivity. If signs of hypersensitivity develop, discontinue Activase. ( 5.2 ) Consider the risk of reembolization from the lysis of underlying deep venous thrombi in patients with pulmonary embolism. ( 5.3 ) Cholesterol embolism has been reported rarely in patients treated with thrombolytic agents. ( 5.4 ) 5.1 Bleeding Activase can cause significant, sometimes fatal, internal or external bleeding, especially at arterial and venous puncture sites. Avoid intramuscular injections and trauma to the patient while on Activase. Perform venipunctures 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 Activase infusion, use an upper extremity vessel that is accessible to manual compression, apply pressure for at least 30 minutes, and monitor the puncture site closely. 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. Fatal cases of hemorrhage associated with traumatic intubation in patients administered Activase have been reported. Aspirin and heparin have been administered concomitantly with and following infusions of Activase in the management of acute myocardial infarction and pulmonary embolism, but the concomitant administration of heparin and aspirin with and following infusions of Activase for the treatment of acute ischemic stroke during the first 24 hours after symptom onset has not been investigated. Because heparin, aspirin, or Activase may cause bleeding complications, carefully monitor for bleeding, especially at arterial puncture sites. Hemorrhage can occur 1 or more days after administration of Activase, while patients are still receiving anticoagulant therapy. If serious bleeding occurs, terminate the Activase infusion and treat appropriately. In the following conditions, the risks of bleeding with Activase 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 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 Activase (e.g., laryngeal edema, rash and shock). Rare fatal outcome for hypersensitivity was reported. Angioedema has been observed during and up to 2 hours after Activase infusion in patients treated for acute ischemic stroke and acute myocardial infarction. In many cases, patients received concomitant angiotensin-converting enzyme inhibitors [see Drug Interactions (7) ] . Monitor patients treated with Activase during and for several hours after infusion for hypersensitivity. If signs of hypersensitivity occur, e.g. anaphyl…

4 CONTRAINDICATIONS 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.

7 DRUG INTERACTIONS 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 )

8.1 Pregnancy Risk Summary Published studies and case reports on alteplase use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Alteplase is embryocidal in rabbits when intravenously administered during organogenesis at the clinical exposure for AMI, but no maternal or fetal toxicity was evident at lower exposure in pregnant rats or rabbits (see Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Maternal Adverse Reactions The most common complication of thrombolytic therapy is bleeding. Pregnancy may increase this risk [see Warnings and Precautions (5.1) ]. Data Animal Data Alteplase is embryocidal in rabbits when administered intravenously during organogenesis in doses (3 mg/kg) approximately equal to the human exposure (based on AUC) at the dose for AMI. No maternal or fetal toxicity was evident at doses (1 mg/kg) approximately 0.3 times the human exposure. In pregnant rats, no maternal or fetal toxicity was evident at doses (1 mg/kg) approximately 0.6 times the human dose for AMI (based on body weight) dosed during the period of organogenesis.

6 ADVERSE REACTIONS 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 …