CATHFLO ACTIVASE

Cathflo ® Activase ® (Alteplase) is a tissue plasminogen activator (t‑PA) produced by recombinant DNA technology. It is a sterile, purified glycoprotein of 527 amino acids. It is synthesized using the complementary DNA (cDNA) for natural human tissue‑type plasminogen activator (t‑PA) obtained from an established human cell line. The manufacturing process involves secretion of the enzyme Alteplase into the culture medium by an established mammalian cell line (Chinese hamster ovary cells) into which the cDNA for Alteplase has been genetically inserted. Cathflo Activase (Alteplase) for injection is a sterile, white to pale yellow, lyophilized powder for intracatheter instillation for restoration of function to central venous access devices following reconstitution with Sterile Water for Injection, USP. Each vial of Cathflo Activase contains 2.2 mg of Alteplase (which includes a 10% overfill), 77 mg of L‑arginine, 0.2 mg of polysorbate 80, and phosphoric acid for pH adjustment. Each reconstituted vial will deliver 2 mg of Cathflo Activase, at a pH of approximately 7.3.

Cathflo ® Activase ® (Alteplase) is indicated for the restoration of function to central venous access devices as assessed by the ability to withdraw blood.

Cathflo ® Activase ® (Alteplase) is for instillation into the dysfunctional catheter at a concentration of 1 mg/mL. • Patients weighing ≥30 kg: 2 mg in 2 mL • Patients weighing <30 kg: 110% of the internal lumen volume of the catheter, not to exceed 2 mg in 2 mL If catheter function is not restored at 120 minutes after 1 dose of Cathflo Activase, a second dose may be instilled (see Instructions for Administration ). There is no efficacy or safety information on dosing in excess of 2 mg per dose for this indication. Studies have not been performed with administration of total doses greater than 4 mg (two 2‑mg doses). Instructions for Administration Preparation of Solution Reconstitute Cathflo Activase to a final concentration of 1 mg/mL: Aseptically withdraw 2.2 mL of Sterile Water for Injection, USP (diluent is not provided). Do not use Bacteriostatic Water for Injection. Inject the 2.2 mL of Sterile Water for Injection, USP, into the 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.

Cathflo Activase should not be administered to patients with known hypersensitivity to Alteplase or any component of the formulation (see DESCRIPTION ).

The following adverse reactions are discussed in greater detail in Section PRECAUTIONS of the label: Bleeding Hypersensitivity In the clinical trials, the most serious adverse events reported after treatment were sepsis (see PRECAUTIONS, Infections ), gastrointestinal bleeding, and venous thrombosis. 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 practice. Trials 1 and 2 The data described for Trials 1 and 2 reflect exposure to Cathflo Activase in 1122 patients, of whom 880 received a single dose and 242 received two sequential doses of Cathflo Activase. In the Cathflo Activase Trials 1 and 2, only limited, focused types of serious adverse events were recorded, including death, major hemorrhage, intracranial hemorrhage, pulmonary or arterial emboli, and other serious 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.

The interaction of Cathflo Activase with other drugs has not been formally studied. Concomitant use of drugs affecting coagulation and/or platelet function has not been studied.