New Standard Reduces Heparin Potency

Beginning next week, heparin shipped to hospitals and pharmacies will be about 10% less potent than that currently available, a change that is likely to have clinical implications when the drug is administered as a bolus IV dose, the FDA said today.

The loss in potency is the result of new manufacturing controls -- including a new reference standard for the drug's unit dose -- adopted by United States Pharmacopeia (USP), a nonprofit standards-setting organization.

The FDA has known for months that the reference standards for heparin would change, but learned only three weeks ago that the change would reduce potency, said John K. Jenkins, MD, director of the office of new drugs, at the FDA's Center for Drug Evaluation and Research.

The difference in potency, which is estimated at about 10% per labeled unit, is unlikely to affect subcutaneous administration because there is a wide range of bioavailability when heparin is administered by that route, he said.

Jenkins said the new standard has been in the works since 2007, when contamination of heparin resulted in hundreds of severe allergic reactions and deaths as well as widespread recalls and shortages.

When USP circulated the new drug monograph for comment during the spring and summer, "there was little concern about clinical significance," but as manufacturers began making heparin using the new standard, one of the companies discovered the difference in potency and informed the FDA, Jenkins said.

The FDA then contacted other manufacturers and confirmed that the reduced potency was observed by all drugmakers using the new reference standard.

At that point, the FDA contacted USP to determine if the rollout of the new standard could be delayed until in vitro and in vivo testing could confirm the exact potency range.

But by then, it was too late. The four makers of heparin -- APP, Hospira, Baxter, and B. Braun -- had all retooled their manufacturing processes to make the drug based on the new standard, which takes effect today.

The best that the FDA could manage was an agreement to delay shipment of the new heparin until Oct. 8, Jenkins said.

To differentiate "new" from "old" heparin once supplies hit the shelves, the four manufacturers have agreed to special labeling on the new product.

Three companies -- APP, the largest manufacturer, which markets heparin in vials; Baxter, which sells the drug in IV bags; and B. Braun, which also markets heparin in IV bags -- have all agreed to add the letter "N" next to the lot number or expiration date on labels of "new" heparin.

The fourth manufacturer -- Hospira which markets heparin in intravenous bags, vials, and syringes -- said it will identify the new heparin with a unique numbering system.

Meanwhile, the FDA is cooperating with the companies to conduct both in vitro and in vivo testing to determine the exact extent of the potency difference. The in vitro tests should be completed in a few weeks, but "animal tests will take longer," said Jenkins. He estimated the in vivo results would be available in less than two months.

But even with those test results, the FDA may not require changes in heparin labeling because dosing of the drug has always been a matter of "individual monitoring of patients" to determine the anticoagulant effect.

Regardless of potency, Jenkins said, heparin should continue to be dosed based on results of patient monitoring.