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The anticoagulant response to warfarin, a narrow therapeutic index drug, increases with age, which may make older patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products. Using US Medicare claims linked to electronic medical records from two large hospitals in Boston, we designed a cohort study of ≥ 65-year-old patients. Patients were followed for a composite effectiveness outcome of ischemic stroke or venous thromboembolism, a composite safety outcome, including major hemorrhage, and a 1-year all-cause mortality outcome. After propensity score fine-stratification and weighting to account for > 90 confounders, hazard ratios comparing brand vs. generic warfarin initiators (95% confidence intervals) for the effectiveness, safety, and all-cause mortality outcomes, were 0.97 (0.65-1.46), 0.94 (0.65-1.35), and 0.84 (0.62-1.13), respectively. Results from subgroup analyses of patients with atrial fibrillation, CHADS-VASc score ≥ 3, and HAS-BLED score ≥ 3 were consistent with the primary analysis., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Background: Warfarin is a commonly used anticoagulant. Whether a given dose of the different formulations of Brazilian warfarin will result in the same effect on the international normalized ratio (INR) is uncertain. The aim of the WARFA trial is to determine whether the branded and two generic warfarins available in Brazil differ in their effect on the INR., Methods: WARFA is a cross-over RCT comparing three warfarins. The formulations tested are the branded Marevan® (Uniao Quimica/Farmoquimica) and two generic warfarin (manufactured respectively by Uniao Quimica Farmaceutica Nacional and Laboratorio Teuto Brasileiro). All of them were manufactured in Brazil, are available in all settings of the Brazilian healthcare system and were purchased from retail drugstores. Eligible participants had atrial fibrillation or flutter, had been using warfarin for at least 2 months with a therapeutic range of 2.0-3.0 and had low variability in INR results during the 1st period of the trial. Our primary outcome, for which we have an equality hypothesis, is the difference between warfarins in the mean absolute difference between two INR results, obtained after three and 4 weeks with each drug. Our secondary outcomes, that will be tested for inequality (except for the mean INR, which will be tested for equality), include the difference in the warfarin dose, and time in therapeutic range. Clinical events and adherence were also recorded and will be reported., Discussion: To our knowledge, WARFA will be the first comparison of the more readily applicable INR results between branded and generic warfarins in Brazil. WARFA is important because warfarins are commonly switched between in the course of a chronic treatment in Brazil. Final results of WARFA are expected in May 2017., Trial Registration: ClinicalTrials.gov NCT02017197 . Registered 11 December 2013.

Purpose: Generic switching of warfarin was recently repealed in Denmark, as adverse drug reaction (ADR) reports suggested risk of excessive anticoagulation following switches from branded to generic warfarin. We investigated this putative association in a formalized pharmacoepidemiological analysis., Methods: We conducted a nationwide cohort study based on Danish healthcare registries, including data from the introduction of generic warfarin until the repeal (January 2011-April 2015). We followed Danish warfarin users over time and compared the rate of incident hospitalizations due to excessive anticoagulation (i.e. increased INR or any bleeding requiring hospitalization) in periods following a recent switch to generic warfarin to the rate in periods without a recent switch., Results: We included 105,751 warfarin users, filling a total of 1,539,640 prescriptions for warfarin (2.5% for generic warfarin). This constituted 89.0% of all warfarin prescriptions in Denmark during the study period. We observed 19,362 switches to generic warfarin during the study period. The adjusted hazard ratio for excessive anticoagulation following a recent switch from branded to generic warfarin was 1.1 (95%CI, 0.8-1.4). The result was robust within subgroups and several sensitivity analyses., Conclusion: Switching from branded to generic warfarin is not associated with an increased risk of hospitalization with excessive anticoagulation. However, a minor excess risk of transient INR increase cannot be excluded. Pharmacoepidemiological studies provide an effective method for swift evaluation of hypotheses generated by ADR-reports., (Copyright © 2015 John Wiley & Sons, Ltd.)

Patent protection for enoxaparin has expired. Generic preparations are developed and approved for clinical use in different countries. However, there is still skepticism about the possibility of making an exact copy of the original drug due to the complex processes involved in generating low-molecular-weight heparins. We have undertaken a careful analysis of generic versions of enoxaparin available for clinical use in Brazil. Thirty-three batches of active ingredient and 70 of the final pharmaceutical product were obtained from six different suppliers. They were analysed for their chemical composition, molecular size distribution, in vitro anticoagulant activity and pharmacological effects on animal models of experimental thrombosis and bleeding. Clearly, the generic versions of enoxaparin available for clinical use in Brazil are similar to the original drug. Only three out of 33 batches of active ingredient from one supplier showed differences in molecular size distribution, resulting from a low percentage of tetrasaccharide or the presence of a minor component eluted as monosaccharide. Three out of 70 batches of the final pharmaceutical products contained lower amounts of the active ingredient than that declared by the suppliers. Our results suggest that the generic versions of enoxaparin are a viable therapeutic option, but their use requires strict regulations to ensure accurate standards.

In the United States, the Food and Drug Administration (FDA) has allowed makers of biologic therapies to use the abbreviated new drug application, which does not require safety and efficacy studies. Instead this relies on proving equivalency with the original compound and demonstrating in vitro activity and similar pharmacodynamics. In the United States, a low-molecular-weight heparin, enoxaparin, was recently approved in a generic format through the abbreviated new drug application. We present a patient treated with branded enoxaparin for 4 years with no complications. After the switch to the generic enoxaparin, the patient developed 2 life-threatening hemorrhages within 4 months of the initiation of the compound. This case suggests that the FDA should follow the European Medicine Administration (EMA) guidance by tightening its approval process for generic bioequivalents and requiring studies demonstrating similar safety and efficacy as the parent compound, prior to approval of a generic biologically active compound.

Many clinicians have expressed concerns about the bioequivalence of warfarin products, and data suggest that substituting warfarin products may increase the risk of major bleeding and thromboembolic complications. Anecdotal reports and some retrospective studies have reported differences in anticoagulation control after a warfarin product substitution. But the best available evidence-prospective, randomized, blinded clinical trials-has failed to validate these observations. Indeed, interpatient and intrapatient variability in anticoagulation control observed before and after warfarin product substitution is very similar. So, while differences in product standardization, bioavailability, and bioequivalence make a convenient explanation, the problem lies elsewhere. Perhaps poor communication, fractionated systems of care, and errors are the culprits.

Background: Substitution of generic warfarin for imprint warfarin (Coumadin; DuPont/Bristol-Myers Squibb) has been a controversial issue due to bioavailability and bioequivalence concerns., Objective: To assess the risk of thrombotic and hemorrhagic events following substitution of warfarin formulations in patients with atrial fibrillation (AF)., Methods: Historical cohort analysis was performed using a commercial insurance claims database. Adults with a diagnosis of AF between January 2003 and December 2007, with 16 or more months of continuous eligibility, a warfarin prescription within 30 days after index AF diagnosis, and at least 3 warfarin prescription fills during the follow-up period were included. Individuals with AF diagnosis or warfarin prescription during the pre-index period were excluded. Cox proportional hazard regression models controlling for sex and baseline comorbidities (Charlson comorbidity index, CCI) were used to evaluate the risks of thrombotic and hemorrhagic events following warfarin formulation switches., Results: Of 37,756 subjects included in the analysis (mean age 70.96 years, 42.3% females), 12,996 (34.4%) switched warfarin formulations, 20,292 (53.7%) used only 1 generic product, and 4468 (11.8%) used only Coumadin during follow-up. Compared with continued use of Coumadin, switching from that product to the generic formulation was associated with a significantly higher risk of thrombotic events (HR = 1.81; 95% CI 1.42 to 2.31). Similar findings were observed for switching from generic warfarin to Coumadin (HR = 1.76; 95% CI 1.35 to 2.30), and from 1 generic to another generic product (HR = 1.89; 95% CI 1.57 to 2.29). Similarly, switching from Coumadin to generic warfarin (HR = 1.51; 95% CI 1.17 to 1.93), generic warfarin to Coumadin (HR = 1.60; 95% CI 1.23 to 2.1), and from 1 generic to another generic product (HR = 1.74; 95% CI 1.45 to 2.11) were associated with significantly higher risk of hemorrhage than remaining on Coumadin., Conclusions: Switching warfarin formulations exposed patients with AF to a higher risk of bleeding events compared to remaining on a single product. Maintaining patients on a product with consistent bioavailability may optimize the risk-benefit balance of anticoagulation therapy.

Background: Vitamin K antagonist tablets are often split to fractionate the dose by elderly patients. We performed a study in order to assess the divisibility of one dosage strength of score-lined warfarin and of score-lined fluindione., Methods: Due to a recent change in the pharmaceutical form of fluindione in order to improve the divisibility, the study was performed over 2 different periods (with the « old » and with the « new » pharmaceutical form). In each period, 10 patients mean aged 82 years, 10 relatives, 10 nurses, 10 medical doctors) were asked to split in half warfarin tablets (W2 1(st) period et W2 2(d) period) and fluindione tablets (F2 et F'2), and to split fluindione tablets into 4 fragments (F4 et F'4). The first end-point was the accuracy of splitting estimated by the difference between the real and the expected weight of fragmented tablets. The statistical analysis was performed using an ANOVA test with 2 variables, subject and drug. The difference between the 2 periods were analyzed using an ANOVA test with 2 variables, subject and period., Results: Over the 2 periods, the differences between real and expected weight were of 4.65% for W2 1(st) phase, 9.48% for F2, 15.35% for F4, 5.56% for W2 2(d )period, 4.30% for F'2, and 6.98% for F'4. The quality of splitting was statistically poorer in the elderly patient group compared to other subjects., Conclusion: This study was not design to assess the clinical relevance (bleeding or thromboembolism) or the anticoagulation control of the variations in drug mass due to inappropriate splitting of tablets. However, split form of drugs should be prescribe with caution to elderly patients.

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.

The recent health care changes and approval of a generic low-molecular-weight heparin (LMWH) by the US Food and Drug Administration (FDA) merit a review of the facts regarding the new and generic anticoagulants. Fatal hypotension from anaphylactoid type reactions following heparin administration was responsible for more than 149 deaths all over the world. Researchers detected a heparin-like semisynthetic contaminant, over-sulfated chondroitin sulfate (OSCS), that appeared to be intentional. Low-molecular-weight heparins are produced using unfractionated heparin and OSCS has been found in various batches of LMWHs. Some newer anticoagulants are claiming to be free from the need to monitor for therapeutic effect and bleeding risk. Therefore, monitoring assays are not being developed and there is no antidote to reverse bleeding. In addition, there are concerns about reproducibility, product variation, and quality. In conclusion, although the generic LMWHs and newer anticoagulants may appear to be effective for qualified indications, their safety remains to be a concern.

Introduction: Compositional variations among biosimilar enoxaparin could lead to a differential immunogenic response between these preparations., Methods: Enoxaparin (Clexane, n = 110) and a biosimilar version (Cutenox, n = 110) were administered to healthy volunteers in Brazil, 40 mg subcutaneous (SQ), daily, for 10 days. Blood was collected at baseline, days 1 and 10, and analyzed for antiheparin/PF4 antibody (AHPF4 antibodies) titers and subtypes by enzyme-linked-immunosorbent serologic assay (ELISA)., Results: Low-molecular-weight heparin (LMWH) treatment resulted in AHPF4 antibodies generation, with differences on day 10 (P < .05). Antibody subtyping (immunoglobulin [Ig] G, IgA, IgM) demonstrated different profiles between LMWH with statistical significance for IgG (Clexane 10 = 0.21 ± 0.06, Cutenox 10 = 0.28 ± 0.10, P < .0001) and IgA (Clexane 10 = 0.15 ± 0.02, versus Cutenox 10 = 0.13 ± 0.02, P < .0001) on day 10, with a significant drug effect (P < .0001) and significant time by drug interaction (P = .0009). All antibody titers were stated in terms of optical density (OD) units., Conclusion: LMWHs immunogenic potential varies to generate AHPF4 antibodies and subtypes and cross-reactivity with preformed antibodies. Such parameters may be useful in defining the biosimilar LMWHs bioequivalence. Future studies evaluating the immunogenicity of biosimilar drugs are warranted.

Background: Because interactions with warfarin represent a serious risk to patients, drug information sources used by clinicians should contain accurate, timely, and practical drug interaction information., Objective: The aim of this study was to assess the information regarding warfarin interactions that is included in the official labeling of prescription products that interact with warfarin., Methods: We examined the official labeling information approved by the US Food and Drug Administration for the 50 drugs, biologics, and drug classes that were commonly identified by 3 drug information compendia--Clinical Pharmacology, ePocrates(®), and Micromedex(®)--and the warfarin US prescribing information (PI) as having an interaction with warfarin. The PI of each product was assessed for possible mention of an interaction with warfarin. The data were collected and tabulated by 1 investigator. A clinical investigator evaluated the data for accuracy and consistency. Unresolved issues were discussed with a third investigator and decided by consensus. The interaction listings were compared to determine similarities, differences, and inconsistencies and analyzed by 5 investigators., Results: Of the labeling for 73 products evaluated, 62 (85%) included mention of an interaction with warfarin. Those failing to mention the warfarin interaction were for older generic drugs or influenza vaccine. Among the labels listing an interaction with warfarin, the location of the information, the terminology used, and the inclusion of evidence for the interaction was inconsistent . When considering the PI for all 73 products, Fleiss' kappa coefficient (κ = 0.467) suggested moderate concordance according to the method of Landis and Koch., Conclusion: This assessment of official US product labeling for 50 drugs, biologics, and drug classes known to interact with warfarin, comprising 73 distinct agents, found that 15% failed to mention the interaction, even though the interaction was mentioned in the warfarin labeling., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

Background: Anticoagulation is an essential part of the management of numerous cardiovascular conditions. Although warfarin sodium has been in clinical use for >40 years, only 1 proprietary warfarin preparation was in use for long-term anticoagulation in Taiwan until 2001, when the Taiwan Food and Drug Administration approved a new generic formulation., Objective: This study evaluated the efficacy and tolerability of switching from an established dose of the branded warfarin sodium product (in mg/wk) to the same dose of the generic product., Methods: This was a randomized, observer-blinded,crossover study in Taiwanese patients who received a mechanical heart valve to replace an original valve or a previously implanted mechanical valve from March 2003 to August 2004 and had received branded warfarin therapy for >/=2 months postoperatively, with a mean baseline international normalized ratio (INR) in the range from 1.7 to 3.0 in the 8- to 12-week run-in period. Patients were randomized to 1 of 2 treatment sequences, each involving three 28-day periods: the generic product for 1 period followed by the branded product for 2 periods, or the branded product for 1 period followed by the generic product for 2 periods. Prothrombin time and INR were measured, and anticoagulant activity was compared. At each visit, treatment-emergent adverse events were recorded and evaluated by the blinded observer, an internal medicine physician who was not involved in patients' care., Results: Thirty-five patients were enrolled (25 men, 10 women; mean age, 52.4 years [range, 34.5-74.4 years]). All but 2 of the patients had received a replacement for a natural heart valve. Thirty-four patients (16 who received the generic product initially, 18 who received the branded product initially) completed the study without a dose change and were >/=75% compliant with therapy. There was no difference in pooled mean (SE) INR between the 2 products (2.28 [0.06] and 2.27 [0.06], respectively). The 90% CI for the difference was 96.4 to 104.9, well within the range for bioequivalence (80-120). There were no differences in the adverse-event profiles of the 2 formulations., Conclusions: No therapeutic inequivalence was demonstrated in this small, single-blind study, suggesting that the generic and branded warfarin products studied were equally effective in maintaining anticoagulation in patients with mechanical prosthetic heart valves. The 2 products had similar safety profiles.

Objective: Our objective was to examine possible changes in the effectiveness of warfarin after a nationwide generic substitution of formulations in 1998., Methods: In the computerized records of a health maintenance organization database, we identified 975 patients who took warfarin continuously over two 6-month periods, before (period 1) and after (period 2) the generic switch. In this sample we performed a retrospective, between-period paired comparison of warfarin doses dispensed and international normalized ratio (INR) levels maintained, as well as of the apparent warfarin sensitivity index (calculated as INR/Warfarin dose [in milligrams per day])., Results: Overall, for period 2, doses were 26.5% higher and INR 4.2% lower, with a 14.7% reduction in warfarin sensitivity index (P <.001). The findings were strongest in the 61 of 975 patients (6.3%) dispensed the lowest maintenance doses (<1.0 mg/d), with minimal change at greater than 3 mg/d. In 94 other patients (9.6%) in whom doses were unchanged, INR (median with 5th and 95th percentiles) dropped to subtherapeutic levels, from 2.2 (1.8, 3.0) to 1.7 (1.3, 1.8) (P <.001). There were no adverse events, expressed as no change in hospital admissions. Apparent warfarin sensitivity was reduced in period 2 by 15% to 20% (P <.001) across all period 1 INR levels., Conclusion: Because a general unidirectional change in INR response per unit warfarin dose cannot be explained by biologic mechanisms or confounding, we conclude that slightly reduced bioavailability (within the acceptable bioequivalence range) of the new formulation led to overestimated period 2 doses and reduced apparent warfarin sensitivity in all patient subgroups (by period 1 dose or INR), which was most prominent in those individuals with the lowest maintenance dose requirements.

Background: Substitution of generic warfarin for Coumadin presents safety concerns due to warfarin's narrow therapeutic index and because a prior generic formulation was removed from the US market after it was associated with adverse events., Objective: To determine whether a health maintenance organization (HMO) can add generic warfarin to its formulary without adversely affecting warfarin management or increasing adverse events., Design: In a prospective, observational study, an HMO that formerly dispensed only Coumadin added a generic warfarin preparation (Barr Laboratories, Pomona, NY) to its formulary., Setting: An anticoagulation service (ACS) affiliated with an HMO that was based in St. Louis, MO., Participants: The cohort consisted of 182 enrollees in the ACS as of May 1, 1999. At the start of the study, these participants were taking Coumadin; by October 31, 2000, all had switched to Barr warfarin., Measurements and Main Results: We collected data 8 months prior to and 10 months after the introduction of generic warfarin for the following endpoints: international normalized ratio (INR) control, frequency of INR monitoring, number of dose changes, and rate of thrombotic and hemorrhagic events. Statistical process control charts were used to differentiate between random variation in the endpoints and changes due to different warfarin formulations, and we used the Wilcoxon signed-rank test to look for a change in any endpoint after patients changed to generic warfarin. No significant differences were found in any endpoint., Conclusions: Substitution of Barr warfarin for Coumadin did not significantly affect INR control, warfarin management, or adverse events. Our findings suggest that HMOs can safely substitute at least 1 generic formulation of warfarin without extra monitoring.

The effectiveness and safety of switching warfarin sodium products in a cohort of patients at a managed care organization were studied. Consecutive patients seen during routine visits at two anticoagulation clinics were requested to voluntarily use a generic warfarin sodium product (Barr Laboratories) instead of Coumadin (Dupont Pharma) for eight weeks. All patients who had received anticoagulation therapy with Coumadin for more than three months, who had a target International Normalized Ratio (INR) of 2.0-3.0 or 2.5-3.5, and who had an INR in the target range at the baseline visit were eligible for the study. The control group was composed of patients who were eligible for the study but were not asked to switch to the generic product or declined to switch products. There were 105 patients in each study group. The before-and-after differences in INR between the conversion group and the control group were small and of negligible clinical importance. Compared with the period before the product switch, the variability of the INR in patients in the conversion group was not significantly different after the switch. Of the 210 patients in the study, only 24 had a change in INR of >1.0 after the baseline visit; in each case, a factor not related to the product switch was associated with the INR change. Use of a generic warfarin sodium product (Barr Laboratories) in patients previously receiving the innovator product (Dupont Pharma) did not change the INRs more than did continued use of the innovator product by another group of patients.