Genentech Cathflo Activase Approved With 30-Minute Dwell Time

Genentech's Cathflo Activase (alteplase) was approved Sept. 4 with a 30-minute dwell time for clearing blocked catheters and ports.

Labeling instructs health care providers to assess function of the central venous access device (CVAD) 30 minutes after administering the drug by attempting to aspirate blood. "If the catheter is not functional" at 30 minutes, it should be checked after 120 minutes of dwell time. If the CVAD is still not clear, a second dose may be used.

The Cathflo Activase BLA was submitted Sept. 29, 2000, and supported by two studies in patients with improperly functioning CVADs: a 150-patient, double-blind, randomized trial that used a two-hour dwell time - Cardiovascular thrombolytic to Open Occluded Lines (COOL) - and a 995-patient, open-label, single-arm trial that used a 30 minute dwell time - COOL II (Pharmaceutical Approvals Monthly, Feb. 2001, p. 18).

In the studies, 68% of patients with occlusions less than 14 days old had CVAD clearing after one dose and 88% had clearing after two doses. For occlusions longer than 14 days, 57% of CVADs cleared after one dose and 72% cleared after two. The studies used a 2 mg dose, the recommended dose for patients weighing at least 30 kg.

Genentech's Activase, which is indicated for treatment of acute myocardial infarction, acute ischemic stroke and acute massive pulmonary embolism, has been used off-label for catheter clearing since withdrawal of the only drug approved for the use, Abbott's Abbokinase Open-Cath (urokinase).

Genentech pointed out that Cathflo Activase will offer potential cost and time savings to health care providers who were breaking up the larger Activase vials for catheter clearing.

Cathflo Activase is supplied in a 2 mg vial and has an average wholesale price of $75. AWP for the 50 and 100 mg vials of Activase are $1,375 and $2,750, respectively.

Urokinase was pulled from the market in 1999 for good manufacturing practice deficiencies related to potential contamination with infectious agents. Abbott anticipates re-launching Abbokinase in the first half of 2002 after clearance of an upcoming sNDA.

Abbokinase Open-Cath is labeled for a 5-minute dwell time. Health care providers are instructed to "wait at least 5 minutes before attempting to aspirate the drug and residual clot with the empty syringe. Repeat aspiration attempts every 5 minutes. If the catheter is not open within 30 minutes, the catheter may be capped allowing Abbokinase solution to remain in the catheter for an additional 30 to 60 minutes before again attempting to aspirate." A second injection may be given if the first does not clear the catheter.

Genentech launched Cathflo Activase Sept. 24. The firm is targeting physicians in oncology, hemodialysis, renal disease, parenteral nutrition, and interventional radiology.

Genentech plans further studies in hemodialysis patients. Labeling notes that patients with hemodialysis catheters were excluded from both sBLA studies. Cathflo was studied in single-, double- and triple-lumen catheters and implanted ports. Genentech also is exploring development of an Activase-coated catheter.

The potential patient population for Cathflo Activase is 750,000, according to Genentech figures. The firm estimates that about 5 mil. CVADs are placed each year in the U.S. and that a quarter of these become clogged. Approximately 60% of those clogs are caused by formation of a blood clot.

In the two clinical trials, "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," labeling states.

The "most serious adverse events reported after treatment were sepsis, gastrointestinal bleeding and venous thrombosis." Sepsis was reported in five of 1,122 patients; gastrointestinal bleeding and venous thrombosis were reported in three patients each.

Unlike Activase labeling, Cathflo labeling contains no warnings, and the only contraindication is in patients with known hypersensitivity to the drug. Labeling says that "circulating plasma levels of alteplase are not expected to reach pharmacologic concentrations" as the drug does not enter systemic circulation. Labeling precautions include avoiding vigorous suction when assessing catheter occlusion and exercising caution in patients with or at risk of internal bleeding.

Cathflo was tested in 312 patients age 65 and over, including 103 who were over 75. Pediatric patients between the ages of two and 16 numbered 126, with 65 of them weighing 10 kg and 30 kg. "There was insufficient enrollment…to draw any conclusions regarding relative efficacy in the pediatric or low weight subgroups, relative efficacy related to catheter types used in these patients, or relative rates of adverse events," according to labeling.

FDA asked for safety and efficacy data in children younger than two and more data on those two to 16 as a Phase IV requirement. The company will submit its protocol for the open label pediatric registry by Nov. 30 and begin enrollment by May 1, 2002. The final study report is due Jan. 2005.

The company will also submit a protocol for monitoring shipping to ensure that Cathflo is delivered before 10:30 a.m. if outside temperature is forecast to exceed 100° F. Genentech will also identify "all other Genentech products that will be shipped under this revised" standard operating procedure.