Alteplase, recombinant

Alteplase is an enzyme (serine protease) that has the property of fibrin-enhanced conversion of plasminogen to plasmin. It produces limited conversion of plasminogen in the absence of fibrin. Alteplase binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin, thereby initiating local fibrinolysis. 1

In patients with acute myocardial infarction administered 100 mg of Activase as an accelerated intravenous infusion over 90 minutes, plasma clearance occurred with an initial half-life of less than 5 minutes and a terminal half-life of 72 minutes. Clearance is mediated primarily by the liver. 2

When Cathflo Activase is administered for restoration of function to central venous access devices according to the instructions in DOSAGE AND ADMINISTRATION , circulating plasma levels of Alteplase are not expected to reach pharmacologic concentrations. If a 2 mg dose of Alteplase were administered by bolus injection directly into the systemic circulation (rather than instilled into the catheter), the concentration of circulating Alteplase would be expected to return to endogenous circulating levels of 5-10 ng/mL within 30 minutes. 1

Two clinical studies were performed in patients with improperly functioning central venous access devices (CVADs). A placebo-controlled, double-blind, randomized trial (Trial 1) and a larger open-label trial (Trial 2) investigated the use of Alteplase in patients who had an indwelling CVAD for administration of chemotherapy, total parenteral nutrition, or long-term administration of antibiotics or other medications. Both studies enrolled patients whose catheters were not functioning (defined as the inability to withdraw at least 3 cc of blood from the device) but had the ability to instill the necessary volume of study drug. Patients with hemodialysis catheters or a known mechanical occlusion were excluded from both studies. Also excluded were patients considered at high risk for bleeding or embolization (see PRECAUTIONS , Bleeding ), as well as patients who were younger than 2 years old or weighed less than 10 kg. Restoration of function was assessed by successful withdrawal of 3 cc of blood and infusion of 5 cc of saline through the catheter.

Trial 1 tested the efficacy of a 2 mg/2 mL Alteplase dose in restoring function to occluded catheters in 150 patients with catheter occlusion up to 24 hours in duration. Patients were randomized to receive either Alteplase or placebo instilled into the lumen of the catheter, and catheter function was assessed at 120 minutes. Restoration of function was assessed by successful withdrawal of 3 cc of blood and infusion of 5 cc of saline through the catheter. All patients whose catheters did not meet these criteria were then administered Alteplase, until function was restored or each patient had received up to two active doses. After the initial dose of study agent, 51 (67%) of 76 patients randomized to Alteplase and 12 (16%) of 74 patients randomized to placebo had catheter function restored. This resulted in a treatment-associated difference of 51% (95% Cl is 37% to 64%). A total of 112 (88%) of 127 Alteplase-treated patients had restored function after up to two doses.

Trial 2 was an open-label, single arm trial in 995 patients with catheter dysfunction and included patients with occlusions present for any duration. Patients were treated with Alteplase with up to two doses of 2 mg/2 mL (less for children who weighed less than 30 kg, see DOSAGE AND ADMINISTRATION ) instilled into the lumen of the catheter. Assessment for restoration of function was made at 30 minutes after each instillation. If function was not restored, catheter function was re-assessed at 120 minutes. Thirty minutes after instillation of the first dose, 516 (52%) of 995 patients had restored catheter function. One hundred twenty minutes after the instillation of the first dose, 747 (75%) of 995 patients had restored catheter function. If function was not restored after the first dose, a second dose was administered. Two hundred nine patients received a second dose. Thirty minutes after instillation of the second dose, 70 (33%) of 209 patients had restored catheter function. One hundred twenty minutes after the instillation of the second dose, 97 (46%) of 209 patients had restored catheter function. A total of 844 (85%) of 995 patients had function restored after up to 2 doses.

Similar rates of catheter function restoration were seen among all catheter types studied (single-, double-, and triple-lumen, and implanted ports).

There were no gender differences observed in the rate of catheter function restoration. Results were similar across age subgroups, but there was insufficient enrollment of pediatric patients to draw any conclusions regarding relative efficacy in pediatric patients (see PRECAUTIONS , Pediatric Use ).

Across both trials, 796 (68%) of 1043 patients with occlusions present for less than 14 days had restored function after one dose, and 902 (88%) had function restored after up to two doses. Of 53 patients with occlusions present for longer than 14 days, 30 (57%) patients had function restored after a single dose, and a total of 38 patients (72%) had restored function after up to two doses.

Three hundred forty-six patients who had successful treatment outcome were evaluated at 30 days after treatment. The incidence of recurrent catheter dysfunction within this period was 26%.

None.

Cathflo Activase is supplied as a sterile, lyophilized powder in 2 mg vials.

Each Cathflo Activase carton contains one 2 mg vial of Cathflo Activase (Alteplase): NDC 50242-041-64.

Each Novaplus™ Cathflo Activase carton contains one 2 mg vial of Novaplus™ Cathflo Activase (Alteplase): NDC 50242-041-65.

1. Collen D, Lijnen HR. Fibrinolysis and the control of hemostasis. In: Stamatoyannopoulos G, Nienhui AW, Majerus PW, Varmus H, editors. The molecular basis of blood diseases, 2nd edition. Philadelphia: Saunders, 1994:662-88.
2. Tanswell P, Tebbe U, Neuhaus K-L, Glasle-Schwarz L, Wojick J, Seifried E. Pharmacokinetics and fibrin specificity of alteplase during accelerated infusions in acute myocardial infarction. J Am Coll Cardiol 1992;19:1071-5.
3. Califf RM, Topol EJ, George BS, Boswick JM, Abbottsmith C, Sigmon KN, et al., and the Thrombolysis and Angioplasty in Myocardial Infarction Study Group. Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of acute myocardial infarction. Am J Med 1988;85:353-9.
4. Bovill EG, Terrin ML, Stump DC, Berke AD, Frederick M, Collen D, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI), phase II trial. Ann Int Med 1991;115:256-65.

Cathflo Activase (Alteplase)                                       7289101

Manufactured by:                                                                  LB0551

Genentech, Inc.                                                                (4821101)

1 DNA Way                                          Revision Date October 2002

                                                FDA Approval Date September 2001

South San Francisco, CA 94080-4990

                                                                      © 2002 Genentech, Inc.

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