The U.S. Food and Drug Administration (FDA) is alerting healthcare providers of a change to the United States Pharmacopeia (USP) monograph for heparin, effective October 1, 2009. Manufacturers will not begin shipping heparin products manufactured and tested according to the new USP monograph until October 8th or later. This change—largely in response to the 2007-2008 heparin contamination problem—will include a new USP reference standard and test method that is used to determine the potency of the drug. The new test method, unlike the previous method, is able to detect impurities that may be present in heparin. The monograph change will also harmonize the USP unit dose with the WHO International Standard (IS) unit dose.
The manufacturing and testing requirements under the new monograph will lessen the potential for contamination of heparin and enhance the production of a high quality drug. However, harmonization of the standard will result in approximately a 10% reduction in the potency of the heparin marketed in the United States.
The change in heparin potency may have clinical significance in some situations, such as when heparin is administered as a bolus intravenous dose and an immediate anticoagulant effect is clinically important. In such situations healthcare providers should consider the change in potency of heparin when making decisions about what dose to administer. The change in heparin potency is expected to be less clinically significant when it is administered subcutaneously due to the low and highly variable bioavailability of heparin when administered by this route. Healthcare providers should also be aware of the decrease in heparin potency as they monitor the anticoagulant effect of the drug; more heparin may be required to achieve and maintain the desired level of anticoagulation in some patients.
Healthcare providers should be aware of the potency change for heparin products manufactured and tested according to the new USP monograph, and the possible clinical effects of this decrease in potency per USP unit dose.
FDA has asked all manufacturers to label their new products in a manner that will help healthcare providers differentiate them from the old products. Labels of most heparin products made according to the new standard will have an “N” in the lot number or following the expiration date. Products manufactured by Hospira can be identified by the number “82” or higher (e.g., 83, 84) at the start of their lot numbers.
The USP is an official standards setting organization for prescription and over–the–counter (OTC) medicines sold in the United States. USP sets standards for the quality, purity, strength, and consistency of medicinal products.
FDA wants to highlight some important information and clinical recommendations during this time of transition:
- There will be simultaneous availability of heparin manufactured to meet the “old” and “new” USP monograph, with potential differences in potency. This overlap of products on the market is necessary to make certain that there is an adequate supply of heparin available for all patients. Products using the new “USP unit” potency definition are anticipated to be available on or after October 8. FDA is working with the manufacturers of heparin to ensure that an appropriate identifier is placed on heparin made under the new USP monograph. Most manufacturers will place an “N” next to the lot number.
- Consider the potential potency variation when administering heparin, particularly in situations where assurance of aggressive anticoagulation is essential to treat or prevent life-threatening thromboses. Clinicians should now consider the potential for up to 10% estimated decrease in heparin activity per “USP unit” when deciding what dose to administer in such cases.
- The potency change may require more frequent or intensive aPTT or ACT monitoring.
- Clinical judgment is essential in determining dose of heparin. Heparin dosing is always individualized to the patient-specific situation. The FDA-approved labeling for heparin has not changed, including the recommended doses. Individualization of heparin dosing has long been the standard for clinical use of the drug and FDA reiterates the importance of clinical judgment in heparin dosing.
FDA is working with the heparin manufacturers to study the impact of this variation in potency and will make the results available when the studies have concluded.