Abstract

The use of generic drugs has become increasingly common in clinical practice. However, for drugs with a narrow therapeutic index, such as warfarin, there may be some concern regarding the definition of bioequivalence. Clinical studies that compared brand name and generic warfarin products provided conflicting results. Therefore, we performed a systematic review of the literature to better assess the characteristics of each generic warfarin product. Several sources were searched, including MEDLINE and EMBASE, electronic records of meetings' abstracts, and reference lists of included articles. Articles were considered relevant if they were original studies, enrolled patients receiving oral anticoagulant treatment, and compared any approved generic warfarin with brand name warfarin in at least one clinical, laboratory, or management outcome. Eleven studies, with a total of more than 40,000 patients, were included; five were randomized controlled trials, and six were observational studies. In three crossover trials evaluating the mean difference of the international normalized ratio (INR) after switching to the alternate formulation of warfarin, no statistically significant difference was found between patients randomly assigned to receive brand name or generic warfarin. The two other randomized trials found no significant differences in the magnitude or number of dosage changes between patients switched to brand name or generic warfarin. The results of the observational studies are more conflicting, suggesting different features for different generic warfarin products. In these observational studies, the time in the therapeutic range and the number of thromboembolic and hemorrhagic complications were similar in studies that compared the anticoagulation control before and after the switch to a generic warfarin product. In one observational study, however, a change in therapeutic INR control after the switch to generic warfarin was reported at the individual patient level. The results of our systematic review suggest that generic warfarin products may be as safe and effective as brand name products and that patients may be safely treated with these products. However, closer monitoring may be reasonable when switching brands, as variations in individual INR response may be seen.
Introduction

The use of generic drugs has become increasingly common in clinical practice after their initial approval more than 20 years ago. Generic drugs represent less expensive bioequivalent versions of brand name drugs and are produced and marketed after the patent on the brand name equivalent expires. A generic drug must meet bioequivalence criteria and be approved based on standards established by the United States Food and Drug Administration (FDA). To be considered bioequivalent to the brand name version, the FDA requires the 90% confidence intervals (CIs) for the rate and extent of absorption of the generic drug to be within 80125% of the mean rate and extent of absorption of the brand name product.[1] This definition of bioequivalence is concerning for drugs with a narrow therapeutic index, defined as those drugs with the following characteristics: presence of less than a 2-fold difference between median lethal dose and median effective dose values, presence of less than a 2-fold difference between the minimum effective and the minimum toxic doses in the blood, and need for careful titration and patient monitoring for safe and effective use of the drug product.[2] Warfarin, the most commonly used oral anticoagulant drug, is a drug with a narrow therapeutic index. In observational studies that evaluated the effects of switching from brand name to generic warfarin, increased rates of clinical events, increased international normalized ratio (INR) instability, and increased need for INR monitoring were noted.[35] Other studies failed to find any statistically significant differences in the quality of INR control between brand name and generic warfarin.[68] This uncertainty has generated confusion among clinicians working in anticoagulation clinics, as well as among patients. To address this important issue, a recent systematic review and meta-analysis of brand name and generic drugs used in cardiovascular disease, including warfarin, was performed to consider the aggregate effect sizes for each drug category.[9] The meta-analysis failed to show a statistically significant difference between brand name and generic warfarin. However, the results of that metaanalysis are provided as an aggregate effect size only; separate analyses of clinical, laboratory, and management variables were not performed. We considered it important to provide separate estimates of the different outcomes evaluated in studies that compared the effects of any generic versus brand name warfarin. Therefore, we performed a systematic review of the results of clinical trials and observational studies and that enrolled patients receiving oral anticoagulant therapy and compared generic with brand name warfarin. Our goal was to compare clinical, laboratory, and management outcomes measured in these studies.