Heparin contaminant linked to adverse events identified.

The chemical compound oversulfated chondroitin sulfate is the contaminant in batches of heparin that has been linked to 19 deaths and several hundred serious health problems in the United States, according to information presented by the Food and Drug Administration in a press conference on March 19.

"At the moment we don't know definitively whether the contaminant was introduced intentionally or by accident," said Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research.

Now that the heparinlike contaminant has been identified, the FDA intends to move forward to determine how and when it was introduced into the supply chain. The contaminant was first discovered in batches of product imported to the United States from a Chinese facility that derives heparin from pig intestines.

"We are continuing to investigate how this got in, and it doesn't appear to be from the pig," Dr. Woodcock said. "And still to be determined is whether the oversulfated chondroitin sulfate, when combined with heparin, can produce the reactions of the sort reported to the FDA," she added.

Compendial tests will enable manufacturers to detect trace amounts of the oversulfated chondroitin sulfate, which should not be confused with natural chondroitin sulfate, a natural substance commonly used to manage joint pain. The oversulfated version can be made relatively cheaply and easily by chemically modifying natural chondroitin sulfate, said Mohab Nasr, Ph.D., director of the FDA's Office of New Drug Quality and Assessment.

China's state food and drug administration has been briefed on the findings. Chinese regulators have been cooperative and have agreed to assist the FDA with its ongoing investigation, Dr. Woodcock said.

The FDA continues to identify, hold, and examine all shipments of heparin entering the United States and test those that raise concerns, she said.

The FDA continues to receive reports of adverse events associated with heparin. To date, a total of 785 serious adverse events have been reported, and not all of these have been evaluated. "Up to" 46 deaths have been reported, but Dr. Woodcock said at a previous press conference that many of the reports do not fit the allergic adverse event criteria, which are related to anaphylaxis and hypotension.

There have been no additional reports of death associated with the contaminated product since it was recalled on Feb. 28, 2008.

The FDA had previously announced that Baxter had stopped making multiple-dose vials of heparin because of an increase in reports of severe allergic reactions in patients receiving bolus injections of the company's heparin, but the vials were not recalled then because of concern that there would not be enough heparin available.

"We feel that doctors and patients can be confident that the product on the market for large volume uses of heparin has been tested and is safe," Dr. Woodcock said.

To report adverse events and for information on the timing of reports of adverse events and deaths related to the contaminated heparin, visit www.fda.gov/cder/drug/ infopage/heparin/default.htm.

BY HEIDI SPLETE

Senior Writer