New Heparin Potency Assay May Have Clinical Impact

Cheryl A. Thompson

BETHESDA, MD 01 October 2009—Manufacturers of heparin-containing pharmaceuticals for the U.S. market have started using a new assay and reference standard that, according to the United States Pharmacopeia (USP), eliminates a roughly 10% difference between U.S. and international heparin units. While USP said it does not expect this change in heparin potency to have clinical significance, FDA said the change "may have clinical significance in some situations."

Those situations, FDA said in a public health alert issued today, include injection of an i.v. bolus dose of heparin to achieve an immediate anticoagulant effect.

The new assay and reference standard are part of the USP heparin sodium monograph that went into effect today.

To help health care providers prepare for the change in heparin potency, FDA has asked manufacturers to wait until October 8 or later to start shipping heparin products manufactured and tested in accordance with the new monograph, John K. Jenkins, director of FDA's Office of New Drugs, said during a media briefing.

"This delay will allow health care providers and pharmacies time to make the necessary adjustments in their prescribing and dispensing practices," he said.

"Clinicians," he said, "should now consider the potential for up to a 10% estimated decrease in heparin activity per USP unit."

FDA is also working with the manufacturers to ensure that their new heparin products have an identifier to help health care providers differentiate the old products from the new ones, Jenkins said. Hospira decided to identify its new heparin products by lot number, he said; lot numbers that start with the digits "82" or higher signify products made in accordance with the new heparin monograph. Other manufacturers, he said, agreed to put the letter "N" in the lot number or after the expiration date.

Clinicians selecting a dose of heparin to achieve an immediate anticoagulant effect should be aware that the potency of the drug, if manufactured in accordance with the new monograph, will be 10% less than in the past, FDA advised.

Also, clinicians monitoring patients' activated partial thromboplastin time (aPTT) or activated clotting time may need to do so more frequently.

"More heparin may be required to achieve and maintain the desired level of anticoagulation in some patients," Jenkins said.

FDA, he said, cannot make specific dosing recommendations for the adjustments because it lacks the requisite clinical data.

The agency said it expects the change in heparin potency to be "less clinically significant" in situations when the drug is given subcutaneously.

Ann K Wittkowsky, director of anticoagulation services at University of Washington Medical Center in Seattle, said clinicians should continue to monitor the aPTT no sooner than six hours after an i.v. bolus dose, initiation of therapy, or a change in dosage.

She said there could be a problem if a patient receives continuous i.v. heparin from a large-volume container of old product one day and from a container of new product the next day but has his or her aPTT monitored only every 24 hours.

But the resultant difference in the aPTT—a crude test of a drug's effects—may only be seconds, she said.

"Also," Wittkowsky said, "there is a tremendous amount of variability in response to heparin because of its poor bioavailability, both intravenously and subcutaneously."

Heparin binds to plasma proteins and other cellular structures, which alters its bioavailability, she said.

"If you put a person on a heparin drip and check aPTT every hour . . . you get a different number every single time," Wittkowsky said.

The impetus for incorporating the new assay and reference standard into USP's heparin sodium monograph was the "heparin adulteration crisis of 2007/2008," USP said in a letter (PDF) dated August 21.

As part of the effort to improve the standards for heparin in this country, USP decided to calibrate its new heparin sodium reference standard to the international standard issued by the World Health Organization. USP said the potency of the USP heparin unit and the international unit had drifted by about 10% over the past 30 years.

Wittkowsky noted that Canada has been interchanging heparin products from the United States and elsewhere for years without problem.

"I think FDA is being incredibly cautious . . . by saying, 'We're making this change; we don't have data to support that there will be any change in patient response; be aware that the change has been made in case anything's observed," she said.

USP did not provide details regarding its estimation of the clinical impact of the new heparin monograph.