Are all warfarin preparations Alike? A comprehensive overview of current data, emerging opinions, and perspectives.

Abstract

The Food and Drug Administration (FDA) ~rst approved the use of generic warfarin sodium tablets by Barr Laboratories in March 1997. This resulted in controversy over whether narrow therapeutic index drugs can be safely interchanged. For many years, there has been only one oral warfarin sodium product available by DuPont Pharma (Wilmington, DE) under the brand name Coumadin®. Adding to this controversy was the approval of a second generic formulation of warfarin sodium tablets in October 1998 manufactured by Apothecon (division of Bristol-Myers Squibb Company, Princeton, NJ). In most states all three warfarin sodium products are considered interchangeable (AB rated) unless the physician speci~es that the brand is medically necessary by writing “No Substitution” on the prescription. This editorial discusses the issues surrounding the substitution of generic warfarin sodium for brand warfarin sodium (Coumadin), and whether consistent and safe anticoagulation can be maintained if these products are interchanged. Warfarin sodium (warfarin) has been used since the early 1950s for its anticoagulant effects. Indications include prevention and/or treatment of venous thromboembolism in a variety of cardiovascular conditions. Few would disagree that warfarin requires careful monitoring and dose adjustments to maintain proper anticoagulant effects. The international normalized ratio (INR) is the standard method for monitoring oral warfarin therapy, with most indications requiring an INR between 2.0 and 3.0. The risk of bleeding is greatly increased with an INR of greater than 5.0, while a subtherapeutic INR (less than 2.0) increases the risk of thromboembolism [1]. A patient’s response to warfarin is in_uenced by a number of factors, including age, patient compliance, vitamin K intake, alcohol consumption, concomitant disease states, and drug interactions [1,2]. All of these patient-speci~c factors may increase or decrease the INR, making a patient at risk for bleeding or thromboembolism, respectively. Variations in tablet strength from lot to lot may also result in variations in a patient’s response. Therefore, the FDA has established speci~c requirements for tablet content uniformity that are published in the United States Pharmacopeia (USP) [3]. The content of each tablet tested is determined by high-performance liquid chromatography. Both the brand and generic manufacturers of warfarin tablets must comply with these speci~cations. The speci~cations require that 10 tablets be tested from every lot and contain 85–115% of the labeled strength and have a standard deviation (SD) of ,6%. If 1 of the 10 tablets falls outside the range or exceeds the SD, 20 more tablets must be tested. The lot is considered acceptable if the SD for all 30 tablets is ,7.8% and not more than 1 tablet is outside the 85–115% range and no tablets are outside a 75–125% range. In the case of Coumadin tablets, DuPont sets stricter standards than those required by the FDA (Teresa P. Dowling, Professional Services, DuPont Pharma, 1999). DuPont requires the 10 tablets tested from each lot to be within 92.5–107.5% of the labeled claim and to have a SD of ,3%. If 1 tablet falls outside these guidelines then, like the FDA requirements, 20 more tablets are tested. DuPont Pharma considers its lot acceptable if the SD of all 30 tablets is ,3.9% and not more than 1 tablet is outside the 92.5–107.5% range and no tablets are outside an 87.5–112.5% range. The important question that arises is, will the generic warfarin manufacturers, Barr and Apothecon, adhere to the USP standards or will they adopt more stringent speci~cations for tablet content uniformity? If the USP standards are utilized by the generic manufacturers, there is a possibility that overlap may occur between the two different dosage units (Fig. 1) [4]. For example, a 2-mg tablet of warfarin meeting USP standards could contain as little as 1.7 mg or as much as 2.3 mg of warfarin. A 2.5-mg tablet meeting USP standards could contain as little as 2.13 mg or as much as 2.88 mg of warfarin. With DuPont’s stricter standards the possibility of tablet overlap is essentially eliminated. Barr Laboratories and Apothecon were contacted to determine the standards of tablet content uniformity they are utilizing when manufacturing their warfarin tablets. According to Barr Laboratories’ Medical Information Department, Barr is complying with the same tablet content uniformity standards as DuPont Pharma and has ~led a supplemental NDA to the FDA in April 1999 to of~cially document these speci~cations