And 'biological mechanism' that leads to adverse reactions identified, officials add
MONDAY, April 21 (HealthDay News) -- Contaminated heparin products have now been found in at least 10 countries, not including the United States, leading to ongoing surveillance measures to ensure the safety of the blood thinner, U.S. health officials announced Monday.
In addition, officials said contaminated lots of the blood thinner have been traced to 12 different Chinese companies that were somehow involved in heparin manufacture. Officials believe a man-made chemical called oversulfated condroitin sulfate -- or OSCS -- may be responsible for dozens of deaths and hundreds of adverse reactions in the United States associated with contaminated heparin between roughly last November and February. The heparin was marketed by Baxter International Inc., of Deerfield, Ill.
"We do not know where the contamination occurred but we do know ... of at least 12 Chinese firms that are in the supply chain for contaminated heparin," Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, said at a news conference.
According to the FDA, contaminated heparin has now been linked to as many as 81 deaths and hundreds of injuries in United States, and well as some incidents in Germany.
Woodcock also announced that the FDA has identified a likely "biological mechanism" by which the oversulfated condroitin sulfate leads to the adverse reactions observed. Those reactions include difficulty breathing, nausea or vomiting, excessive sweating and falling blood pressure, and life-threatening shock.
Woodcock's announcement seemed to conflict with statements made earlier Monday by Chinese officials who said that oversulfated condroitin sulfate was not responsible for the reported injuries and deaths.
"We are aware that our Chinese colleagues are skeptical that such a link has been established. We are hoping to have further dialogue to present data as we work together to resolve this complex situation," Woodcock said.
Also Monday, the FDA issued a warning letter to the Changzhou SPL Company Ltd., which supplies heparin to Baxter International, stating that its manufacturing equipment was "unsuitable for its intended use" and that the company did not adequately scrutinize its own suppliers.
Changzhoi and its parent company, Scientific Protein Laboratories (SPL) of Waunakee, Wisc., expressed "regret" at the FDA's warning letter. "We do not believe that the warning letter reflects Changzhou SPL's actual state of compliance with current good manufacturing practices in the heparin Active Pharmaceutical Ingredient (API) industry, or the positive findings in prior third-party audits of the facility... Changzhou SPL is committed to cooperating with FDA and will promptly provide a detailed response to the warning letter," SPL said in a prepared statement.
The statement added that the contaminant found in certain lots of heparin was not introduced in the manufacturing processes at Changzhou SPL or at SPL, but earlier in the supply chain.
There have been no reports of adverse events in the other countries that turned up contaminated heparin: Australia, Canada, China, Denmark, France, Germany, Italy, Japan, the Netherlands and New Zealand, the FDA said.
Most of the reactions in the United States have taken place at hemodialysis centers, almost exclusively involving kidney patients receiving a "bolus dose," which is a high dose of heparin administered over a short period of time, according to the FDA.
Despite identification of the contaminant at 12 Chinese companies, FDA officials stressed that they don't know where in the supply chain the oversulfated condroitin sulfate may have been introduced.
And not all contaminated Heparin emerged from Baxter International, Woodcock said.
But FDA officials are fairly sure that oversulfated condroitin sulfate is responsible for the problems seen late last year and early this year.
Raw heparin is derived from pig intestines, and it's often processed by small, unregistered mom-and-pop workshops in China. Heparin is used for certain types of surgery to prevent blood clots. Kidney patients also take it before undergoing dialysis.
Oversulfated condroitin sulfate mimics heparin's qualities and is a modified form of chondroitin sulfate. Condroitin sulfate is a naturally occurring substance made from animal cartilage and is often used in supplements to treat arthritic joints. But, oversulfated chondroitin sulfate is man-made and doesn't occur naturally.
"The fact that we have established a mechanism by which this [oversulfated condroitin sulfate] might cause adverse events we think strengthens the association considerably," Woodcock said. "In the test tube, if we use heparin with OSCS, we see changes in blood mediators that could lead to this reaction. In addition, this has been observed in animals, and we just heard today from another group of experts that they have also observed this so we think this story is starting to come together."
For now, however, the U.S. heparin supply seems to be safe, she said.
"The heparin supply in the U.S. is tested and is free of this contaminant," Woodcock said. "We now feel that we have a mechanistic link so we feel that testing requirements put into place will prevent reoccurrence of this event."
The U.S. National Library of Medicine has more on heparin.
SOURCES: April 21, 2008, news conference with Janet Woodcock, M.D., director, Center for Drug Evaluation and Research, U.S. Food and Drug Administration; April 21, 2008, prepared statement, Scientific Protein Laboratories, Waunakee, Wisc.
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