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Veterinarians concerned about FDA’s hydroxyethyl starch warning

U.S. regulators impose limits on HES; proposed European ban in flux


July 17, 2013
By: Jennifer Fiala
For The VIN News Service



Photo courtesy of Dr. John Daugherty, Poland Veterinary Centre
Colloidal solutions such as VetStarch are indicated to treat hypovolemia associated with low blood albumin concentrations. They also can be used to raise blood pressure in patients undergoing anesthesia or suffering blood loss.
When a patient presents with severe blood loss or shock, Dr. Tony Johnson often does what many veterinarians do in emergency situations. He administers the intravascular volume expander hetastarch as a first-line treatment.

“It's sort of viewed as the miracle cure for shock,” he said of the solution’s animal health application.

This cornerstone in fluid therapy — a popular colloid solution known by its chemical name, hydroxyethyl starch (HES) — is generating uncertainty from veterinarians across the country as federal regulators warn its use can cause mortality or severe renal disease in some human patients.

Last month, the U.S. Food and Drug Administration (FDA), reacting to recent data showing that HES solutions may cause kidney injury and death in certain cases, advised against administering the drug to critically ill adult patients with preexisting renal dysfunction or sepsis or who are undergoing open heart surgery in association with cardiopulmonary bypass.

FDA is requiring pharmaceutical companies to affix a black box warning — the agency’s strongest alert — on package inserts or literature describing HES products. Such alerts signify that medical studies indicate that the drug carries a significant risk of serious or life-threatening adverse effects.

That’s left veterinarians wondering about the safety of administering hydroxyethyl starches off-label to their patients. Several FDA-approved HES preparations are marketed in the United States for use in humans. Hetastarch, a generic brand of HES made by Teva Pharmaceuticals, is one commonly used by veterinarians.

On the Veterinary Information Network (VIN), an online community for the profession, veterinarians expressed confusion about how to treat the FDA warning.

“I don't feel we could manage a septic peritonitis with severe hypoalbuminemia without colloids,” wrote Dr. Thomas Day, an anesthesiologist and emergency practitioner in Oregon, Wis. “… I've never heard of any hydroxyethyl starch product in our profession causing renal damage.”

Johnson, a clinical assistant professor at Purdue University's veterinary college, said he feels “torn," leaning toward heeding the FDA's warning by curbing his use of colloids.

“... On the other hand, we don't have veterinary data, and this may not apply,” Johnson wrote on VIN.

When asked about the warning’s crossover to animal health, a spokeswoman with the FDA’s Center for Veterinary Medicine said the agency could not advise veterinarians because HES is not approved for use in animals.

“FDA has not evaluated and approved the safety and effectiveness of a veterinary version of hetastarch, and so use of hetastarch in veterinary medicine would be considered extralabel use," agency officials said by email. "Therefore, FDA does not have further information on whether the boxed warning on increased mortality and severe renal injury in human patients would also apply to animals.”

Dr. Kim Buck, a practitioner at the Animal Emergency Room in San Antonio, said she uses VetStarch, a synthetic HES colloid indicated to treat or prevent hypovolemia (low blood volume).

“How do we know that VetStarch does not cause kidney injury in pets?” she asked on VIN. “Most of the studies that are performed in veterinary medicine are very limited.”

Officials with Abbott Animal Health, maker of the VetStarch, explained that the colloid is a tetrastarch, not a hetastarch, with key characteristic differences including molecular weight and molar substitution. The company said it has not received any reports of adverse events identified in the FDA’s black box warning.

FDA could not corroborate the statement about adverse events because VetStarch is not approved by the agency — a finding the National Institutes of Health confirms on DailyMed, its website about marketed drugs.

"This drug has not been found by FDA to be safe and effective, and this labeling has not been approved by FDA," reads DailyMed's online disclaimer.

Even so, VetStarch is advertised as "FDA approved for use in dogs and cats." When asked about the discrepancy, Abbott officials did not respond.

FDA said by email that that agency is aware there are "many unapproved drug products marketed for use in animals."

"FDA considers a variety of factors in determining whether to take action against an unapproved animal drug and doesn't comment on actions in regard to particular products," officials stated.
 
Considering the data on using HES solution in humans, Abbott says veterinarians should be cautious when using VetStarch in patients with renal impairment. “As stated in our package insert, ‘VetStarch is mainly excreted by the kidneys, and the risk of adverse reactions to the drug may be greater in patients with impaired renal function,’ ” Abbott said in a statement.

Abbott supports the opinion of Dr. Deborah Silverstein, an associate professor of small animal critical care at the University of Pennsylvania School of Veterinary Medicine.

“There is no evidence at this time to suggest that the use of hydroxyethyl starch solutions in small animals increases the risk of mortality or renal dysfunction,” she said by email. “Fortunately, the incidence of severe acute kidney injury in critically ill dogs and cats is much lower than that seen in human intensive care units.”

In European Union countries, whether HES solutions will remain available is under question. EU drug regulators have suggested an outright ban. The impetus for the action came via a recommendation from the European Medicine Agency’s Pharmacovigilance Risk Assessment Committee, which concluded, “the benefits of infusion solutions containing hydroxyethyl starch (HES) no longer outweigh their risks...”

It’s up to another EU body, the Coordination Group for Mutual Recognition and Decentralised Procedures-Human, to make final regulatory decisions. However, objections from some EU member nations pushed the Pharmacovigilance Risk Assessment Committee to reconsider its proposal to suspend the marketing of HES in Europe. According to a statement issued last week, a re-review is under way and the committee’s previous recommendation is “on hold.”

Johnson, the Purdue University veterinarian, notes that doctors can treat shock using other intravenous fluids known as crystalloids, solutions typically comprised of mineral salts or other water-soluble molecules.

"Good old usual normal everyday IV fluids are unaffected by all this," he said.






VIN News Service commentaries are opinion pieces presenting insights, personal experiences and/or perspectives on topical issues by members of the veterinary community. To submit a commentary for consideration, email news@vin.com.



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