cathflo activase vial, directing the diluent stream into the powder. slight foaming is not unusual; let the vial stand undisturbed to allow large bubbles to dissipate. mix by gently swirling until the contents are completely dissolved. complete dissolution should occur within 3 minutes. do not shake. the reconstituted preparation results in a colorless to pale yellow transparent solution containing 1 mg/ml cathflo activase at a ph of approximately 7.3. cathflo activase contains no antibacterial preservatives and should be reconstituted immediately before use. the solution may be used for intracatheter instillation within 8 hours following reconstitution when stored at 2–30°c (36–86°f). no other medication should be added to solutions containing cathflo activase. instillation of solution into the catheter inspect the product prior to administration for foreign matter and discoloration. withdraw 2 ml (2 mg) of solution from the reconstituted vial. instill the appropriate dose of cathflo activase (see dosage and administration ) into the occluded catheter. after 30 minutes of dwell time, assess catheter function by attempting to aspirate blood. if the catheter is functional, go to step 7. if the catheter is not functional, go to step 5. after 120 minutes of dwell time, assess catheter function by attempting to aspirate blood and catheter contents. if the catheter is functional, go to step 7. if the catheter is not functional, go to step 6. if catheter function is not restored after one dose of cathflo activase, a second dose of equal amount may be instilled. repeat the procedure beginning with step 1 under preparation of solution. if catheter function has been restored, aspirate 4–5 ml of blood in patients ≥10 kg or 3 ml in patients <10 kg to remove cathflo activase and residual clot, and gently irrigate the catheter with 0.9% sodium chloride injection, usp. any unused solution should be discarded . stability and storage store lyophilized cathflo activase at refrigerated temperature (2–8°c/36–46°f). do not use beyond the expiration date on the vial. protect the lyophilized material during extended storage from excessive exposure to light.

us adverse events not thought to be attributed to underlying disease or concurrent illness. major hemorrhage was defined as severe blood loss ( > 5 ml/kg), blood loss requiring transfusion, or blood loss causing hypotension. non‑serious adverse events and serious events thought to be due to underlying disease or concurrent illness were not recorded. patients were observed for serious adverse events until catheter function was deemed to be restored or for a maximum of 4 or 6 hours depending on study. for most patients the observation period was 30 minutes to 2 hours. spontaneously reported deaths and serious adverse events that were not thought to be related to the patient's underlying disease were also recorded during the 30 days following treatment. four catheter-related sepsis events occurred from 15 minutes to 1 day after treatment with alteplase, and a fifth sepsis event occurred on day 3 after alteplase treatment. all 5 patients had positive catheter or peripheral blood cultures within 24 hours after symptom onset. three patients had a major hemorrhage from a gastrointestinal source from 2 to 3 days after alteplase treatment. one case of injection site hemorrhage was observed at 4 hours after treatment in a patient with pre-existing thrombocytopenia. these events may have been related to underlying disease and treatments for malignancy, but a contribution to occurrence of the events from alteplase cannot be ruled out. there were no reports of intracranial hemorrhage. three cases of subclavian and upper extremity deep venous thrombosis were reported 3 to 7 days after treatment. these events may have been related to underlying disease or to the long-term presence of an indwelling catheter, but a contribution to occurrence of the events from alteplase treatment cannot be ruled out. there were no reports of pulmonary emboli. there were no gender-related differences observed in the rates of adverse reactions. adverse reactions profiles were similar across all age subgroups. trial 3 in trial 3 all serious adverse events were recorded with a specific interest in intracranial hemorrhage, major hemorrhage, thrombosis, embolic events, sepsis and catheter related complications. major hemorrhage was defined as severe blood loss ( > 5 ml/kg), blood loss requiring transfusion, or blood loss causing hypotension. non-serious adverse events were not recorded. patients were observed until catheter function was deemed to be restored or for a maximum of 4 hours after the first dose. additionally, serious adverse events were elicited from patients at 48 hours (up to 96 hours) following completion of treatment. no pediatric patients in trial 3 experienced an intracranial hemorrhage, major hemorrhage, thrombosis, or an embolic event. three cases of sepsis occurred 2 to 44 hours after treatment with cathflo activase. all of these patients had evidence of infection prior to administration of cathflo activase. an additional patient developed fever and lethargy within one day of cathflo activase administration, which required outpatient intravenous antibiotics. in one subject, the lumen of the catheter, placed 2 years previously, ruptured with infusion of the study drug. there were no gender-related differences observed in the rates of adverse reactions. adverse reactions profiles were similar across all age groups.

c 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).

f 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.