CATHFLO ACTIVASE Powder for solution for injection Ref.[10768] Active ingredients: Alteplase

Long‑term studies in animals have not been performed to evaluate the carcinogenic potential or the effect on fertility. Short-term studies that evaluated tumorigenicity of Alteplase and effect on tumor metastases were negative in rodents. Studies to determine mutagenicity (Ames test) and chromosomal aberration assays in human lymphocytes were negative at all concentrations tested. Cytotoxicity, as reflected by a decrease in mitotic index, was evidenced only after prolonged exposure at high concentrations exceeding those expected to be achieved with Cathflo Activase.

Three 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 predominately adult 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 mL 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 mL of blood and infusion of 5 mL 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 mL of blood and infusion of 5 mL 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% CI 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.

Across Trials 1 and 2, 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%.

Trial 3 was an open‑label, single‑arm trial in 310 patients between the ages of 2 weeks and 17 years. All patients had catheter dysfunction defined as the inability to withdraw blood (at least 3 mL for patients ≥ 10 kg or at least 1 mL for patients <10 kg). Catheter dysfunction could be present for any duration. The indwelling CVADs (single-, double-, and triple‑lumen, and implanted ports) were used for administration of chemotherapy, blood products or fluid replacement, total parenteral nutrition, antibiotics, or other medications. Patients with hemodialysis catheters or known mechanical occlusions were excluded from the study, as were patients considered at high risk for bleeding or embolization. Patients were treated with up to two doses of Cathflo Activase instilled into the catheter lumen. For patients weighing ≥30 kg, the dose was 2 mg in 2 mL. For patients weighing <30 kg, the dose was 110% of the estimated internal lumen volume, not to exceed 2 mg in 2 mL. Restoration of function was assessed at 30 and 120 minutes (if required) after administration of each dose. Restoration of function was defined as the ability to withdraw fluid (3 mL in patients ≥10 kg; 1 mL in patients <10 kg) and infuse saline (5 mL in patients ≥10 kg; 3 mL in patients <10 kg).

The overall rate of catheter function restoration of 83% (257 of 310) was similar to that observed in Trial 2, as were the rates of function restoration at the intermediate assessments.

The three trials had similar rates of catheter function restoration among the catheter types studied (single-, double-, and triple‑lumen, and implanted ports). No gender differences were observed in the rate of catheter function restoration. Results were similar across all age subgroups.