Heparin contaminant detected in drug supply of 11 countries

FDA officials are planning more investigations of Chinese manufacturers.

Contaminated heparin, which has been implicated in increasing adverse events in the United States, has been detected in the drug supplies of 10 other countries, health officials announced at a press conference.

In the latest development of an ongoing recall of heparin products manufactured by Baxter International Inc., Chinese and U.S. officials have confirmed a link between contaminated doses of heparin and a spike in reported adverse reactions and deaths in patients receiving the drug between November 2007 and February 2008. The contaminant, oversulfated chondroiton sulfate, has been found in drug supplies in Australia, Canada, China, Denmark, France, Germany, Italy, Japan, the Netherlands, New Zealand and the United States.

Although a direct causal relationship has not been established, Baxter announced the heparin recall after a disproportionate number of patients who had died after taking heparin were also shown to exhibit one or more allergic or hypotensive symptoms. Health officials have traced the contaminant to several manufacturers in China, although no single entry point in the supply line has been identified. Chinese health officials conceded that the contaminant originated in China, but denied that the contaminant was causing the adverse reactions in the United States.

Expanded recall

Beginning in January 2008, Baxter recalled nine lots of multiple-dose heparin sodium injection lots after observing an increased number of allergic reactions to the product. Baxter expanded its recall to all heparin products and vial sizes in February. Scientific Protein Laboratories also recalled its heparin lots distributed to medical device manufacturers.

There have been 131 deaths reported to the FDA following heparin administration since Jan. 1, 2007, with 123 of the events reported on or after Jan. 1, 2008. The number of reported deaths and allergic reactions has since decreased to pre-recall levels as of March 2008.

The FDA launched an investigation into Baxter and a Scientific Protein Laboratories manufacturing facility in Changzhou, China, which made an active ingredient of Baxter’s heparin. In an April 21 warning letter to the Changzhou manufacturing facility, the FDA said an inspection of the facility found flaws in the processing steps used to remove impurities, inadequate evaluation systems for heparin crude material suppliers, unproven test methods and unsuitable manufacturing equipment.

The FDA has also announced its intent to investigate plants and facilities at other Chinese manufacturers in the near future, pending approval from the Chinese government. – by Eric Raible

There is enough cause for concern for allergic reactions that would definitely make health care providers want to be watchful. Any patient who exhibits low blood pressure, nausea, vomiting — anything that would indicate a reaction to the heparin — will attract more attention. First and foremost, the FDA and manufacturers need to engage in an aggressive screening process to make sure we do not continue to get contaminated heparin into the country. People may also need to examine, for some disease states, alternative therapies. There are some alternative blood thinners out like bivalirudin, enoxaparin and fondiparinux for certain disease states.

– C. Michael Gibson, MD

Chief of Clinical Research
Beth Israel Deaconess Medical Center, Boston