Baxter is providing an update on several
advances related to the investigation into recent heparin adverse reactions
associated with the company’s U.S. vial-based heparin products, which have
since been recalled.

I. Baxter confirms that the contaminant identified in the company’s
U.S. heparin vial products is hypersulfated chondroitin sulfate.

Baxter scientists have provided information to the U.S. Food and Drug
Administration (FDA) that confirms the presence of hypersulfated chondroitin
sulfate in the heparin Active Pharmaceutical Ingredient (API) that was used in
Baxter’s vial-based heparin products in the U.S., which the company fully
recalled.

Chondroitin sulfate is a molecule that occurs naturally and is a major component
of cartilage – the tough, connective tissue that cushions the joints. Chondroitin
sulfate is a common, biologically derived material that is sold in oral form as a
dietary supplement. The substance we found in the affected lots of heparin API
is not a naturally occurring substance, but the hypersulfated version of
chondroitin sulfate, which means that it has been chemically modified, resulting
in a more heparin-like molecule.

This finding is consistent with last week’s update stating that the unknown
material appeared to be a highly sulfated glycosaminoglycan-like (GAG-like)
material. While heparin-like, the material is structurally different from naturallyoccurring
heparin. The hypersulfated chondroitin sulfate has approximately the
same molecular weight as heparin and is similar in other ways, which is why
standard testing did not detect its presence.

II. Baxter scientists have detected the contaminant in crude heparin,
which indicates that the material is introduced in the supply chain
before it reaches the API manufacturer (SPL).

Baxter has collaborated with FDA in the development of sophisticated analytical
procedures, using capillary electrophoresis and nuclear magnetic resonance
spectroscopy technology. Baxter has also applied these sophisticated analytical
procedures to test the crude heparin material, which comes from consolidators,
and has detected the peak in some crude material lots. Consolidators and
workshops handle the crude material used in the manufacture of the heparin API,
and Baxter will continue to seek access to consolidators and workshops that
supply SPL in an effort to understand how hypersulfated chondroitin sulfate was
introduced.

“The hypersulfated chondrointin sulfate is not only found in the active
pharmaceutical ingredient (API) we use to make our heparin, but in the crude
material used to make the API,” said Norbert Riedel, Ph.D., Baxter’s corporate
vice president and chief scientific officer. “That means that this contaminant was
very likely introduced at the workshop or consolidator level, before it reached our
API supplier and definitely before it reached Baxter.”

“We’re at a critical juncture in the investigation and further progress can be
accelerated with the cooperation of the consolidators and workshops,” said
Riedel.

III. Baxter is working on establishing causality between the contaminant
and adverse reactions; tests underway.

While a causal link has not been established, the increase in adverse events has
been associated with lots of the product containing this substance.

To confirm a causal link, the same allergic response must be reproduced in a test
environment. Considering that a very narrow population of patients
(approximately one per 10,000 doses) had an allergic reaction, developing a way
to mimic the clinical environment is difficult.

Baxter has already conducted a number of biologic tests, trying to determine
whether the contaminated API causes allergic reactions.

“So far we have not been able to trigger allergic responses in biologic tests,” said
Riedel. “Given that the rate of reactions associated with the recalled heparin
were reported in approximately one per 10,000 doses, recreating this reaction is
statistically challenging,” he said.

Baxter is continuing its efforts to determine if there is a link between the
contaminant and adverse reactions, using additional advanced tests.

“The remaining questions are how and why hypersulfated chondroitin sulfate was
introduced into heparin crude materials, and whether or not causality can be
established,” said Riedel.

IV. No fatalities have been confirmed by medical evidence to be caused
by allergic reactions to Baxter heparin.

At this point in time, neither Baxter nor the U.S. Food and Drug Administration
(FDA) has confirmed that allergic reactions to Baxter’s heparin have caused any
fatalities. The company determined that there are four cases in which patients
received Baxter heparin and suffered an allergic-type reaction to heparin that
may have contributed to the adverse outcome, though there is not yet enough
medical data available to draw a firm conclusion that the allergic reaction caused
the death. In each of these cases, the patient had multiple, complex medical
conditions. In three of these four cases, patients had either undergone, or were
in the process of undergoing, invasive cardiac surgery. The company has
received approximately 600 heparin-related adverse reaction reports to date.

Baxter International Inc.
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