ACTIVASE RT-PA

1 Dosing Considerations ACTIVASE rt-PA (alteplase for injection) is intended for intravenous use only. It should be given via a dedicated intravenous line with an infusion pump. Extravasation of ACTIVASE rt-PA infusion can cause ecchymosis and/or inflammation.

Management consists of terminating the infusion at the IV site and application of local therapy. Administer ACTIVASE rt-PA as soon as possible after the onset of symptoms. Anticoagulation During and After Treatment with ACTIVASE rt-PA To date, heparin has been administered concomitantly in more than 90% of patients given ACTIVASE rt-PA.

Adjunctive intravenous heparin administration is recommended to obtain a therapeutic partial thromboplastin time (PTT). The infusion of heparin should be initiated prior to the termination of the infusion of ACTIVASE rt-PA. 2 Recommended Dose and Dosage Adjustment There are two dose regimens for ACTIVASE rt-PA for use in the management of AMI.

The comparative efficacy of these two regimens has not been evaluated. 90-MINUTE ACCELERATED INFUSION The recommended total dose is based upon patient weight, not to exceed 100 mg. For patients weighing >67 kg, the recommended dose is 100 mg, administered as a 15 mg intravenous bolus, followed by 50 mg infused over 30 minutes and then 35 mg infused over the next 60 minutes.

50 mg/kg to a maximum of 35 mg infused over the next 60 minutes. This 90-minute infusion regimen is recommended for use up to 6 hours after onset of AMI symptoms. 50 mg/kg over 60 Minutes tPA Total Dose (mg) (Bolus + Maintenance) (Maximum Dose = 100 mg) (lb) (kg) 15 mg (15 mL) over 2 minutes Infusion Dose (mg) (Max Dose = 50 mg) Infusion Rate (mL/hr) Volume to be Infused (mL) Infusion Dose (mg) (Max Dose = 35 mg) Infusion Rate (mL/hr) Volume to be Infused (mL) 90-94 95-97 98-104 105-109 110-114 115-119 120-124 125-129 130-134 135-139 140-144 145-149 >149 41-42 43-44 45-47 48-49 50-51 52-54 55-56 57-58 59-60 61-63 64-65 66-67 >67 15 mL 15 mL 15 mL 15 mL 15 mL 15 mL 15 mL 15 mL 15 mL 15 mL 15 mL 15 mL 15 mL 52 mL 54 mL 57 mL 60 mL 63 mL 65 mL 68 mL 71 mL 73 mL 76 mL 80 mL 83 mL 85 mL 31 32 34 36 38 39 41 43 44 46 48 50 50 62 64 68 72 75 78 82 86 88 92 96 100 100 31 mL 32 mL 34 mL 36 mL 38 mL 39 mL 41 mL 43 mL 44 mL 46 mL 48 mL 50 mL 50 mL 21 22 23 24 25 26 27 28 29 30 32 33 35 21 22 23 24 25 26 27 28 29 30 32 33 35 21mL 22mL 23mL 24mL 25mL 26mL 27mL 28mL 29mL 30mL 32mL 33mL 35mL 67 69 72 75 78 80 83 86 88 91 95 98 100 1 mg = 1 mL 3-HOUR INFUSION The recommended dose is 100 mg administered as 60 mg in the first hour, of which 6-7 mg is administered as a bolus over the first 1-2 minutes and the remainder is administered by continuous infusion, 20 mg by continuous infusion during the second hour, and 20 mg by continuous infusion over the following one to four hours.

1 Adverse Reaction Overview Bleeding: General The most frequent adverse reaction associated with ACTIVASE rt-PA (alteplase for injection) is bleeding. g. g. 02%). A cause and effect relationship has not been established. A rare fatal outcome for hypersensitivity has been reported.

2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. 9%. 7%, not all of which were fatal. 9% (27/3092) in placebo- treated patients. Although the incidence of all strokes, as well as that for hemorrhagic stroke, increased with increasing age, treatment with accelerated regimen of ACTIVASE rt-PA was still shown to reduce mortality in older patients.

2% for streptokinase (subcutaneous heparin) (See Table 1). 0% for streptokinase (subcutaneous heparin) in the GUSTO study. 17 p-value is for pairwise comparison to rt-PA. 4%. 3%. 7%. The maximum total dose of ACTIVASE rt-PA used in the treatment of acute myocardial infarction should not exceed 100 mg.

Death and permanent disability have been reported in patients who have experienced stroke and other serious bleeding episodes. 3 Less Common Clinical Trial Adverse Reactions Not applicable. 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Not applicable.

5 Post-Market Adverse Reactions The following adverse reactions have been reported among patients receiving ACTIVASE in clinical trials and in post marketing experience. These reactions are frequent sequelae of the underlying disease and the effect of ACTIVASE on the incidence of these events is unknown.

General ACTIVASE rt-PA (alteplase for injection) should be administered in a hospital setting where the appropriate diagnostic and monitoring techniques are readily available. Routine management of myocardial infarction should not be deferred after evidence of successful thrombolysis is seen.

Evaluation and management of underlying atherosclerotic heart disease should be carried out as clinically indicated. Non compressible arterial puncture must be avoided. Arterial and venous punctures should be minimized. In the event of serious bleeding, ACTIVASE rt-PA and heparin should be discontinued immediately.

Heparin effects can be reversed by protamine. Bleeding The most common complication encountered during therapy with ACTIVASE rt PA (alteplase for injection) is bleeding. g. venous cutdowns, arterial punctures, sites of recent surgical intervention) The concomitant use of heparin anticoagulation contributes to the risk of bleeding.

Fibrin will be lysed during the infusion of ACTIVASE rt-PA and bleeding from recent puncture sites may occur. Therefore, therapy with ACTIVASE rt-PA, as with other thrombolytic agents, requires careful attention to all potential bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites and needle puncture sites).

PRACTIVASE® rt-PA (alteplase for injection) Page 15 of 44 Intramuscular injections and nonessential handling of the patient should be avoided during and immediately following treatment with ACTIVASE rt-PA. Venipunctures should be performed carefully and only as required.

Should an arterial puncture be necessary during an infusion of ACTIVASE rt-PA, 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.

ACTIVASE rt-PA (alteplase for injection) should not be administered to patients with known hypersensitivity to the active substance alteplase or to any ingredient in the formulation or components of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

ACTIVASE rt-PA (alteplase for injection) therapy is contraindicated in the following situations because of an increased risk of bleeding: • Active internal bleeding PRACTIVASE® rt-PA (alteplase for injection) Page 5 of 44 • History of stroke • Patients receiving other intravenous thrombolytic agents • Recent (within two months) intracranial, or intraspinal surgery or trauma • Intracranial neoplasm, arteriovenous malformation, or aneurysm • Known bleeding diathesis • Severe uncontrolled hypertension (systolic BP > 180 mm Hg and/or diastolic BP > 110 mm Hg) • Recent traumatic cardiopulmonary resuscitation • Recent severe trauma