Generic Warfarin

Warfarin sodium is a highly effective drug for the prevention of thromboembolism in a wide variety of cardiovascular conditions. Marked individual variability in the response of the hemostatic system and the potential for significant interaction with other drugs mandates careful and regular monitoring of patients who receive warfarin. In the past decade, several clinical trials have demonstrated unequivocally the efficacy of warfarin for both the primary and secondary prevention of stroke in patients with atrial fibrillation.1Petersen P Boysen G Godtfredsen J et al.Placebo-controlled randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. the Copenhagen AFASAK Study.Lancet. 1989; 1: 175-179Abstract PubMed Scopus (1676) Google Scholar, 2Boston Area Anticoagulation Trial for Atrial Fibrillation InvestigatorsThe effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation.N Engl J Med. 1990; 323: 1505-1511Crossref PubMed Scopus (1504) Google Scholar, 3Connolly SJ Laupacis AL Gent M et al.Canadian Atrial Fibrillation (CAFA) Study.J Am Coll Cardiol. 1991; 18: 349-355Abstract Full Text PDF PubMed Scopus (1086) Google Scholar, 4Stroke Prevention in Atrial Fibrillation InvestigatorsStroke Prevention in Atrial Fibrillation Study: final results.Circulation. 1991; 84: 527-539Crossref PubMed Scopus (1728) Google Scholar, 5Ezekowitz MD Bridges SL James KE et al.Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation.N Engl J Med. 1992; 327: 1406-1412Crossref PubMed Scopus (1245) Google Scholar, 6EAFT Study GroupSecondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke.Lancet. 1993; 342: 1255-1262PubMed Google Scholar, 7Stroke Prevention in Atrial Fibrillation InvestigatorsWarfarin versus aspirin for the prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study.Lancet. 1994; 343: 687-691Abstract PubMed Scopus (1131) Google Scholar, 8Stroke Prevention in Atrial Fibrillation InvestigatorsAdjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.Lancet. 1996; 348: 633-638Abstract Full Text Full Text PDF PubMed Scopus (1094) Google Scholar In view of the high prevalence of atrial fibrillation in the elderly population (estimated to be 1 to 2% of persons of >70 years of age), the pool of patients who are potential warfarin candidates has both grown and aged. Despite the proven efficacy of warfarin in clinical trials, several observational studies have shown that many physicians are reluctant to give anticoagulants to patients with atrial fibrillation because of concerns, perceived or real, that the potential for major bleeding outweighs the risks of stroke prevention.9Kutner M Nixon G Silverstone F Physicians' attitudes toward oral anticoagulants and antiplatelet agents for stroke prevention in elderly patients with atrial fibrillation.Arch Intern Med. 1991; 151: 1950-1953Crossref PubMed Scopus (148) Google Scholar, 10Bath PMW Prasad A Brown MM et al.Survey of use of anticoagulation in patients with atrial fibrillation.BMJ. 1993; 307: 1045Crossref PubMed Scopus (76) Google Scholar, 11Lip GY Tean KN Dunn FG Treatment of atrial fibrillation in a district general hospital.Br Heart J. 1994; 71: 92-95Crossref PubMed Scopus (123) Google Scholar, 12Laupacis A Sullivan K Canadian Atrial Fibrillation Anticoagulation Study GroupCanadian atrial fibrillation anticoagulation study: were the patients subsequently treated with warfarin?.Can Med Assoc J. 1996; 154: 1669-1674Google Scholar, 13Stafford R Singer DE National patterns of warfarin use in atrial fibrillation.Arch Intern Med. 1996; 156: 2537-2541Crossref PubMed Google Scholar, 14McCrory DC Matchar DB Samsa G et al.Physician attitudes about anticoagulation for nonvalvular atrial fibrillation in the elderly.Arch Intern Med. 1995; 155: 277-281Crossref PubMed Scopus (245) Google Scholar, 15Schlicht JR Davis RC Naqi K et al.Physician practices regarding anticoagulation and cardioversion of atrial fibrillation.Arch Intern Med. 1996; 156: 229-290Crossref Google Scholar The data generated from clinical trials clearly indicate that the benefits of embolic stroke prevention outweigh the risks of major or fatal bleeding by approximately 20 to 1,16Atrial Fibrillation InvestigatorsRisk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials.Arch Intern Med. 1994; 154: 1449-1457Crossref PubMed Scopus (2932) Google Scholar yet valid concerns have been raised about the applicability of controlled trials to clinical practice.17Gottlieb LK Salem-Schatz S Anticoagulation in atrial fibrillation: does efficacy in clinical trials translate into effectiveness in practice?.Arch Intern Med. 1994; 154: 1945-1953Crossref PubMed Google Scholar Such concerns revolve around, among other issues, the belief that patients in clinical trials received tighter anticoagulation control than would normally be obtained and that they constituted a small subgroup of patients characterized by reliability and, potentially, a low bleeding risk. Indeed, review of the atrial fibrillation trials that published information on the percentage of screened patients who entered the trial indicates that all but the AFASAK trial recruited less than 10%. Although there were good reasons for many patients not to be enrolled (such as concomitant conditions that required warfarin therapy), a significant number of the nonenrolled patients were trial candidates, and this low percentage reinforces the notion of the potential difference between patients seen in clinical practice and those in the trials. Despite evidence that many warfarin-eligible patients do not receive anticoagulation, a review of the studies that have addressed this issue9Kutner M Nixon G Silverstone F Physicians' attitudes toward oral anticoagulants and antiplatelet agents for stroke prevention in elderly patients with atrial fibrillation.Arch Intern Med. 1991; 151: 1950-1953Crossref PubMed Scopus (148) Google Scholar, 10Bath PMW Prasad A Brown MM et al.Survey of use of anticoagulation in patients with atrial fibrillation.BMJ. 1993; 307: 1045Crossref PubMed Scopus (76) Google Scholar, 11Lip GY Tean KN Dunn FG Treatment of atrial fibrillation in a district general hospital.Br Heart J. 1994; 71: 92-95Crossref PubMed Scopus (123) Google Scholar, 12Laupacis A Sullivan K Canadian Atrial Fibrillation Anticoagulation Study GroupCanadian atrial fibrillation anticoagulation study: were the patients subsequently treated with warfarin?.Can Med Assoc J. 1996; 154: 1669-1674Google Scholar, 13Stafford R Singer DE National patterns of warfarin use in atrial fibrillation.Arch Intern Med. 1996; 156: 2537-2541Crossref PubMed Google Scholar, 14McCrory DC Matchar DB Samsa G et al.Physician attitudes about anticoagulation for nonvalvular atrial fibrillation in the elderly.Arch Intern Med. 1995; 155: 277-281Crossref PubMed Scopus (245) Google Scholar, 15Schlicht JR Davis RC Naqi K et al.Physician practices regarding anticoagulation and cardioversion of atrial fibrillation.Arch Intern Med. 1996; 156: 229-290Crossref Google Scholar does indicate that acceptability of warfarin therapy for stroke prevention is increasing, with a higher percentage of patients receiving warfarin in late 1990 surveys than in those performed in the earlier part of the decade. Certainly increased awareness of the efficacy of warfarin must have played a role, but this decade has also seen the widespread introduction in the United States of the international normalized ratio (INR) to monitor prothrombin times18Andrews TC Peterson DW Doeppenschmidt D et al.Complications of warfarin therapy monitored by the International Normalized Ratio versus the prothrombin time.Clin Cardiol. 1995; 18: 80-82Crossref PubMed Scopus (13) Google Scholar (thereby reducing a tremendous variability in the degree of anticoagulation that results from the use of thromboplastins with different sensitivity) and a greater reliance on anticoagulation clinics rather than individual practitioner control of warfarin therapy.19Ansell JE Hughes R Evolving models of warfarin management: anticoagulation clinics, patient self-monitoring, and patient self-management.Am Heart J. 1996; 132: 1095-1100Abstract Full Text PDF PubMed Scopus (134) Google Scholar Both of these innovations have been shown to result in improved anticoagulation control and a decreased incidence of major (but not necessarily minor) bleeding.20Palareti G Leali N Coccheri S et al.Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT).Lancet. 1996; 348: 423-428Abstract Full Text Full Text PDF PubMed Scopus (1279) Google Scholar Any physician or nurse who has been responsible for the control of warfarin therapy recognizes the many vagaries of this drug, including interpatient variability of dose, interaction with many other drugs, and fluctuations in the INR associated with intercurrent illnesses, such as an exacerbation of congestive heart failure. The nonlinear pharmacodynamics of warfarin require cautious dosage adjustment to maintain patients within the narrow range of INR wherein bleeding is minimized and antithrombotic effect is maximized.21Hirsh J Dalen JE Deykin D Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.Chest. 1995; 108 (suppl): 231S-246SAbstract Full Text Full Text PDF PubMed Google Scholar, 22European Atrial Fibrillation Study GroupOptimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia.N Engl J Med. 1995; 333: 5-10Crossref PubMed Scopus (497) Google Scholar This demands not only great care on the part of the provider, but also reliance on a drug formulation that is consistently within a very narrow range of bioavailability. In 1980, the unannounced substitution by a hospital pharmacy of amorphous warfarin sodium for crystalline warfarin sodium (Coumadin; Dupont Pharma; Wilmington, DE) in a cost-saving attempt resulted in loss of anticoagulation control in a high proportion of patients monitored in the hospital's anticoagulation clinic.23Richton-Hewett S Foster E Apstein C Medical and economic consequences of a blinded oral anticoagulant brand change at a municipal hospital.Arch Intern Med. 1988; 148: 806-808Crossref PubMed Scopus (46) Google Scholar The resultant increase in the number of patient visits necessitated by this substitution resulted in an increased cost of patient care and in risk of significant bleeding. Amorphous warfarin was subsequently withdrawn from the US market, and crystalline warfarin sodium, produced by a single manufacturer under the brand name Coumadin, has remained the only formulation of warfarin available until now. Recently, generic crystalline warfarin sodium has been approved by the US Food and Drug Administration (FDA) as a therapeutically equivalent drug to Coumadin. Therapeutic equivalence requires not only that the drug is a pharmaceutical equivalent (ie, has identical active ingredients with identical strength and quality) but also that criteria for bioequivalence are met. Bioequivalence testing is usually determined in a small number of normal volunteers, and the FDA permits the therapeutically “equivalent” drug to differ from the pioneer drug by a ratio and extent of absorption between −20 and +25%.24Approved drug products. 17th ed. US Department of Health and Human Services, Washington, DC1997Google Scholar This range may be clinically acceptable for such drugs as antibiotics or even antiarrhythmic agents, for which the therapeutic range is wide and only roughly correlates with efficacy, but is of particular concern when such drugs as warfarin with a narrow therapeutic range7Stroke Prevention in Atrial Fibrillation InvestigatorsWarfarin versus aspirin for the prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study.Lancet. 1994; 343: 687-691Abstract PubMed Scopus (1131) Google Scholar,25Albers GW Atrial fibrillation and stroke: three new studies, three remaining questions.Arch Intern Med. 1994; 154: 1443-1448Crossref PubMed Scopus (209) Google Scholar, 26Ezekowitz MD James KE Stroke Prevention in Atrial Fibrillation II Study [letter].Lancet. 1994; 343: 1508-1509Abstract PubMed Scopus (9) Google Scholar, 27Stroke Prevention in Atrial Fibrillation InvestigatorsBleeding during antithrombotic therapy in patients with atrial fibrillation.Arch Intern Med. 1996; 156: 409-416Crossref PubMed Google Scholar, 28Connolly S Stroke Prevention in Atrial Fibrillation II Study [letter].Lancet. 1994; 343: 1509PubMed Google Scholar are discussed. The potential variation in bioavailability among different brands of warfarin may cause significant problems because minor dose changes in susceptible patients, such as the elderly, can result in clinically significant and potentially life-threatening deviations in the INR. Will the availability of generic warfarin place patients who already receive warfarin at an increased risk if this formulation is used? The answer depends on several factors. These include the closeness of the bioavailability of the generic to the parent product (it is generally the case that generic products fall closer to the innovative product than the −20 to +25% rule allows), the awareness of physicians that more than one warfarin product exists, and most important, the regulations that govern substitution of one manufacturer's product for another. (This problem will be compounded as other manufacturers produce generic warfarin, which may differ from the parent compound and from the initial generic drug.) In the absence of extensive, large-scale, comparative bioavailability and pharmacodynamic data in elderly patients with multiple comorbid conditions29Fihn SD Callahan CM Martin DC et al.The risk for and severity of bleeding complications in elderly patients treated with warfarin.Ann Intern Med. 1996; 124: 79-97Crossref Scopus (543) Google Scholar (a frequent profile in the patient with atrial fibrillation), the cost-benefit ratio of such a switch remains unknown. The potential for inadvertent overdose or underdose of anticoagulation is of concern and may be greatest in those states with mandatory substitution laws or for those patients whose insurer demands such substitution. The introduction of cheaper generic drugs that are truly bioequivalent is to be welcomed, and data that demonstrate such equivalence deserve wide dissemination.30Rennie D Thyroid storm [editorial].JAMA. 1997; 277: 1238-1243Crossref PubMed Google Scholar, 31Dong BJ Hauck WW Gambertoglio JG et al.Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism.JAMA. 1997; 277: 1205-1213Crossref PubMed Google Scholar However, we believe that it is vital that substitution of generic for brand-name warfarin or vice versa should not occur without the practitioner's knowledge and that any such substitution be accompanied by an increased frequency of INR monitoring until stability is achieved. Clinical guidelines for using generic substitutes need to be formulated in order to guarantee patients' safety while maximizing the beneficial effects. Much effort has been invested into proving the utility and safety of warfarin in the prevention of thromboembolic events. An equal effort must now be realized to ensure that generic warfarin does not become a wild card that will set back the gradually improving state of knowledge and practice so carefully built up over the last decade. It will be unfortunate indeed if inadequately informed health-care professionals and their patients permit drug substitutions without the safeguards necessary to provide a smooth transition.