Generic Warfarin Research Articles

Observing INR Results in Patients Who Switched from Brand-Name to Generic Warfarin during the COVID-19 Pandemic at KAMC, Riyadh, Saudi Arabia

Abstract Background: Since the global spread of coronavirus disease 2019 (COVID-19), multiple challenges have faced the medical field, including the suspension of numerous drug companies, leading to a shortage in drug supplies to hospitals. Hospitals were required to use a bioequivalent generic form of a drug for continuing treatment of the patients. Objective: This study assessed the International Normalized Ratio (INR) score for the patients who were switched from Coumadin® (Bristol-Myers Squibb Pharma Company), brand-name warfarin, to a generic form of warfarin in the anticoagulant clinic due to the shortage of Coumadin® during the COVID-19 pandemic. Materials and Methods: A retrospective, cross-sectional chart review study was conducted at King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia. Patients who switched from Coumadin® to generic warfarin from February 2020 to February 2021 were included. This study compared the brand-name and generic forms of warfarin to determine their effectiveness and if the generic form can be used as a therapeutic equivalent. All the data were collected from the electronic health records in KAMC. Each patient file was reviewed for the INR results before and after the switch of warfarin to determine if there was a mean difference between the two variables. Results: In total, 2,197 patients’ medical records were reviewed, yielding 15,499 INR values. The majority (n = 1,362, 80.4%) of the 1,709 mechanical valve INRs were low (INR < 2.1), and 10,697 (77.5%) of the non-mechanical valve INR values were low (INR < 1.6). The Wilcoxon two-sample test was used to evaluate the change in the INR value before and after the switch. The results demonstrate that there is a statistical significance between the effectiveness of Coumadin and generic warfarin. The P values were 0.026 and <0.0001 for the mechanical valve group and the non-mechanical valve group, respectively. Conclusion: The findings of this study indicate that there is a significant difference between the effectiveness of Coumadin and generic warfarin.

Structural Changes of Sodium Warfarin in Tablets Affecting the Dissolution Profiles and Potential Safety of Generic Substitution.

At present, the risk of generic substitutions in warfarin tablets is still being discussed. The aim of this study was to assess whether API interactions with commonly used excipients may affect the safety of generic replacement of warfarin sodium tablets. These interactions were observed during an accelerated stability study, and the effect of the warfarin solid phase (crystalline/amorphous form) as well as the API particle size distribution was studied. Commercial tablets and prepared tablets containing crystalline warfarin or amorphous warfarin were used. In addition, binary mixtures of warfarin with various excipients were prepared. The structural changes before and after the stability study were monitored by dissolution test in different media, solid-state NMR spectroscopy and Raman microscopy. During the stability study, the conversion of the sodium in warfarin to its acid form was demonstrated by some excipients (e.g., calcium phosphate). This change in the solid phase of warfarin leads to significant changes in dissolution, especially with the different particle sizes of the APIs in the tablet. Thus, the choice of suitable excipients and particle sizes are critical factors influencing the safety of generic warfarin sodium tablets.

You cannot always warfawin: a case of significant INR fluctuation with brand to generic conversion of warfarin

Background: Warfarin is affected by many variables such as diet, alcohol, and medications; however, it is unclear if brand to generic conversion may also play a role. This case reports a patient with fluctuating international normalized ratio (INR) while being switched from brand to generic temporarily. Case Presentation: A 60-year-old obese white male taking brand name Jantoven© (warfarin) at home for 9 years at a consistent dose for atrial fibrillation was in hospital for treatment of cellulitis. He was switched to generic warfarin at his home dose on admission. While in hospital, he required dose escalation to three times his home dose to achieve a therapeutic INR. Conclusion: Generic warfarin may have different effects on INR when compared to brand name Jantoven©. More research is warranted to determine if differences may truly exist and potential ways to address the issue. Until then, providers should be cognizant of interchanging the two products to monitor for INR variation.

Frecuencia de sangrado en pacientes con enfermedades cardiovasculares anticoagulados con warfarina genérica vs. Coumadin

* Trabajo ganador del premio al "Mejor trabajo de Residentes" otorgado por el XXI Congreso Colombiano de Medicina Interna. Cali, 14 al 17 de octubre de 2010
 
 Objetivos: comparar la frecuencia de complicaciones hemorrágicas en pacientes mayores de dieciocho años con enfermedades cardiovasculares que se encuentren anticoagulados con warfarina genérica y en aquellos anticoagulados con Coumadin.
 
 Metodología: se realizó un estudio de cohortes de tipo retrospectivo, se tomó una muestra total de 444 pacientes, 222 en terapia con warfarina genérica y 222 en terapia con Coumadin.
 
 Resultados: en la muestra de 444 se conoció el género en 406 pacientes, 187 (46.1%) fueron mujeres y 219 (53.9%) hombres. Los diagnósticos más frecuentes por los cuales los pacientes se encontraban anticoagulados fueron reemplazo valvular 265 pacientes y fibrilación auricular 123 pacientes. De todos los pacientes presentaron alguna complicación 194. Al momento de la complicación se encontraban en tratamiento con warfarina genérica 152 pacientes (78.4%) y 42 pacientes se encontraban en tratamiento con Coumadin (21.6%). De los 194 pacientes que presentaron complicaciones, 114 (58.76%) presentaron algún episodio de sangrado. De ellos, presentaron sangrado mayor siete pacientes y sangrado menor 107 pacientes.. Después de la complicación cambiaron de medicamento 47 pacientes, de los cuales lo hicieron de warfarina genérica a Coumadin 39 pacientes, de los cuales mejoraron 94.9% y de Coumadin a warfarina genérica ocho pacientes, con mejoría sólo en 12.5%.
 
 Conclusiones: la frecuencia de episodios de sangrado menor es significativamente mayor entre los pacientes anticoagulados con warfarina genérica que en los anticoagulados con Coumadin. Además en los pacientes que presentaron alguna complicación, se observó una mejoría significativa con el cambio de warfarina genérica a Coumadin

Healthy User Bias in Comparative Safety Studies for Brand-Name vs. Generic Products: The Example of Warfarin.

Warfarin was selected as a case study to examine confounding when comparing a product across different manufacturers because it is a narrow therapeutic index drug with prevalent beliefs for brand-name superiority. Medicare beneficiaries aged ≥65years with atrial fibrillation and an incident outpatient warfarin prescription from July 2006 through July 2015 were included in the study population (N=746,098). Substantial imbalances were observed between brand-name warfarin and generics for (i) clinical comorbidity, (ii) socioeconomic status, (iii) prescriber specialty, (iv) recent ambulatory and emergent care, (v) drug adherence, (vi) pharmacy setting (e.g., retail, mail-order), and (vii) risk scores for bleeding and thrombosis. Patients receiving brand-name warfarin were healthier than patients receiving generic manufactured warfarin. Utilization of generic warfarin products also differed by geographic region and pharmacy setting. Manufacturer-level comparative-safety studies for causal inference should carefully consider the presence of these imbalances and their potential for introducing healthy user bias.

PUBLIC HEALTH SURVEILLANCE REVEALS AN INCREASE IN HEALTH CARE UTILIZATION FOR GENERIC VS. BRAND-NAME WARFARIN USERS

Even with nowadays many direct oral anticoagulant options, brand-name or generic warfarin is still widely used to prevent atherothrombotic events in cardiology. Federal standards regulate bioequivalence of generic vs. brand-name drugs through comparative bioavailability studies but do not regulate clinical equivalence or tolerability in “real-life” settings. Through our public health surveillance system, we have evaluated the impact of the generic warfarin commercialization on health care utilization: emergency room (ER) consultations or hospitalizations. We did an interrupted time series analysis using the Québec Integrated Chronic Disease Surveillance System, a surveillance system of the second most populous province in Canada (∼8.3 million in 2016). Rates of health care utilization for warfarin users (n=280,158) aged ≥ 66 years were calculated for six-month periods, five years before and up to 15 years after warfarin commercialization (from January 1996 to January 2016). Periods before and after generic warfarin commercialization were compared by negative binomial segmented regression models for all users with a specific variable for generic or brand-name users. Sensitivity analyses were also conducted. Generic warfarin analogs were first reimbursed on January 2, 2001. Over the 20-year period, there was a mean rate of 113 ER or hospitalizations for 100 brand-name or generic users per six-month period, similar before and after generics arrival. After onset of generics reimbursement, there was an immediate increase in rates of health care utilization for generic vs. brand-name users (difference-hospitalizations: 8.0% [95% confidence interval: 1.5% to 14.6%]; ER consultations: 9.1% [4.2% to 14.1%]). Rates of health care utilization remained higher for generic vs. brand-name users up to 15 years after generic warfarin reimbursement, with parallel trends for both outcomes (difference: 0.0% [0.0% to 0.1%]). Sensitivity analyses confirmed the results. Among generic warfarin users, we observed increased rates of health care utilization six months after generics commercialization. Risk and survival analysis studies controlling for potential confounders are required to better characterize generic substitution, as stricter licensing process may be required.

Abstract P146: Public Health Surveillance Reveals an Increase in Health Care Utilization for Generic versus Brand-name Warfarin Users

Background: Even with many direct oral anticoagulant options, brand-name or generic warfarin is still widely used to prevent atherothrombotic events in cardiology. Federal standards regulate bioequivalence of generic vs. brand-name drugs through comparative bioavailability studies but does not regulate clinical equivalence nor tolerability in a “real-life” settings. Through public health surveillance, we have evaluated the impact of the generic warfarin commercialization on health care utilization: emergency room (ER) consultations or hospitalizations. Methods: We used an interrupted time series analysis using the Quebec Integrated Chronic Disease Surveillance System, a surveillance system from the second populous province in Canada (~8.3 million in 2017). Rates of health care utilization for warfarin users (n=280,158) aged ≥ 66 years were calculated for 6-month periods, 5 years before up to 15 years after warfarin commercialization (from January 1996 to January 2016). Periods before and after generic warfarin commercialization were compared by negative binomial segmented regression models for all users with a specific variable for generic or brand-name users. Sensitivity analyses were also conducted. Results: Generic warfarin analogs (n=5) were commercialized from January 2001. There was an approximated mean rate of 1134 ER or hospitalizations for 1000 brand-name and generic users per 6-month period, similar before and after generics commercialization. After generics commercialization, there was an immediate increase in rates of health care utilization for generic (9.9%) vs. brand-name users (0%), a statistically significant difference (9.9% [95% confidence interval: 4.4% to 15.5%], p = 0.0001). Rates of health care utilization remained stable and higher for generic vs. brand-name users throughout the period after generics commercialization. Conclusion: Among generic warfarin users, we observed an increased rates of health care utilization soon after generics commercialization. Risk and survival analysis studies controlling for potential confounders are required to deepen this pharmacovigilance signal as stricter licensing process may be required.

In Vitro Bioequivalence for three Products of Warfarin Sodium in Syrian Market

Three generic warfarin sodium 5mg tablets from different manufacturers had been evaluated to assess their bioequivalence in vitro. Other general quality assessments of these tablets like weight variation, content uniformity, hardness, friability and disintegration time were carried out and all these generic tablets passed these specification tests. To compare the dissolution profiles of all the tablet formulation withthe innovator brand, a model independent approach of difference factor (f1) and similarity factor (f2) was employed with all points included in the in vitro dissolution studies. These results showedthat all generic warfarin sodium tablets included in thisinvestigation were not bioequivalent with the chosen innovator brand, but two generic tablets were bioequivalent between each other.

Integrating In Vitro, Modeling, and In Vivo Approaches to Investigate Warfarin Bioequivalence.

We demonstrate the use of modeling and simulation to investigate bioequivalence (BE) concerns raised about generic warfarin products. To test the hypothesis that the loss of isopropyl alcohol and slow dissolution in acidic pH has significant impact on the pharmacokinetics of warfarin sodium tablets, we conducted physiologically based pharmacokinetic absorption modeling and simulation using formulation factors or in vitro dissolution profiles as input parameters. Sensitivity analyses indicated that warfarin pharmacokinetics was not sensitive to solubility, particle size, density, or dissolution rate in pH 4.5, but was affected by dissolution rate in pH 6.8 and potency. Virtual BE studies suggested that stressed warfarin sodium tablets with slow dissolution rate in pH 4.5 but having similar dissolution rate in pH 6.8 would be bioequivalent to the unstressed warfarin sodium tablets. A four‐way, crossover, single‐dose BE study in healthy subjects was conducted to test the same hypothesis and confirmed the simulation conclusion.

Design and rationale for the WARFA trial: a randomized controlled cross-over trial testing the therapeutic equivalence of branded and generic warfarin in atrial fibrillation patients in Brazil

BackgroundWarfarin 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.MethodsWARFA 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.DiscussionTo 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 registrationClinicalTrials.gov NCT02017197 . Registered 11 December 2013.

PCV21 - Comparative Effectiveness of Brand-Name and Generic Warfarin on Stroke and Bleeding Events in Atrial Fibrillation Patients: A 6-Year Population-Based Retrospective Cohort Study in Taiwan

To determine the stroke and bleeding outcome among generic versus brand name warfarin recipients in a large cohort. This is a nationwide population-based retrospective cohort study using administrative claims data National Health Insurance Research Database in Taiwan. We identified all patients who were diagnosed for AF and used generic or brand name warfarin alone between January 1, 2006, and December 31, 2010 (N=23,141) from the NHIRD. A propensity score matching approach is used to create a subgroup for further adjusting potential selection bias. Cox proportional hazards regressions were performed to estimate the risk of hospitalization for stroke and diagnosis of bleeding associated with the generic versus brand name warfarin recipients. We identified 12,944(55.94%) AF patients who received generic warfarin, and 10,197(44.06%) AF patients who received brand name warfarin. In the matched cohort, the event rate of hospitalization for stroke was 17.44 per 100 person-years for the generic warfarin group, as compared to 15.98 for the brand name warfarin group and the multivariate adjusted hazard ratios (HRs) for hospitalization for stroke of generic warfarin group was 1.15 (95% CI, 1.09-1.20) compared with brand name warfarin group. The adjusted HRs for critical site bleeding, definite bleeding, intracranial bleeding and gastrointestinal bleeding of generic warfarin group were 0.92(95% CI, 0.86-0.99), 0.94(95% CI, 0.90-0.99), 0.92(95% CI, 0.76-1.13) and 0.94(95% CI, 0.89-0.99) respectively in comparison to brand name warfarin group. Generic warfarin group was associated with statistically significantly higher risk for stroke when the prescribed daily dose of warfarin was higher than or equal to 2.5, the multivariate adjusted hazard ratio of generic warfarin group for stroke is 1.14(95% CI, 1.02-1.26). The generic warfarin recipients were at slightly but statistically significant higher risk of hospitalization for stroke and lower risk of bleeding in comparison to brand name warfarin group.

Evaluating Drug Profitability before Market Launch using Pharmacoeconomic Data: A Study of Generic Warfarin used for Long-Term Anticoagulation

Evaluating Drug Profitability before Market Launch using Pharmacoeconomic Data: A Study of Generic Warfarin used for Long-Term Anticoagulation

Tiempo en rango terapéutico (TRT) en clínica de anticoagulación: Reportes de eventos adversos y factores asociados a bajo TRT

In the treatment of warfarin anticoagulation, reduction of thromboembolic events must be evaluated with the risk of bleeding. Time in therapeutic range (TTR) by the method of Rosendaal aluated with the risk of bleeding. Time in therapeutic range (TTR) by the method of Rosendaal is a tool that values quality monitoring anticoagulant therapy and correlates with the presence of thromboembolic events or bleeding. In this study time therapeutic range (TTR), factors associated with lower (TTR) and adverse effects presented in the anticoagulation clinic are presented. Methods and Results: A descriptive cross-sectional study from 1° January 2011 and 29th February 2012.2232 results of INR of 319 patients were assessed. 98550 days follow up. 44% (108) were men, 66% (211) women, average age 60.3 years, seven average visits / year, warfarin weekly dose of 29.8 mg. The weekly dose has an inverse relationship with age; in patients under 45 years 37.9 mg., and in patients over 75 years, 22.1 mg. The TTR increased from 48 to 54%, respectively. Indications for anticoagulation: atrial fibrillation (AF) 38% (121), venous thromboembolic disease (VTE) 35% (112), prosthetic valves (PV) 17.5% (56) and emboli or arterial thrombosis (EA) 9.5% (30). 228 patients (71%) had a TTR average of 64%. (40-100), INR greater than 5 in 2.24% and INR less than 1.5 in 10.9%. Minor bleeding: 16 patients (5%), major bleeding occurred in two patients (0.65%) and one adverse event of embolism (0.32%). The factors associated with low TTR were male gender, venous thromboembolic disease, use of generic warfarin, age less than 55 years, time shorter than one year and less than five visits. Conclusions: TTR is a useful measurement to establish the efficacy of anticoagulant therapy with warfarin. The goal of a 60% TTR ensures fewer adverse effects from bleeding or thrombosis. A low number of visits and anticoagulation less than a year are associated with low TTR.

Generic switching of warfarin and risk of excessive anticoagulation: a Danish nationwide cohort study.

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. 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. 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. 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.

Completeness of prescription information in US commercial claims databases

Pharmacy commercial claims databases are widely used for pharmacoepidemiologic research. However, concerns have been raised that these databases may not fully capture claims for generic medications as a result of patients filling outside the context of their insurance. This has implications for many research activities and quality improvement programs. We sought to estimate the percentage of missing prescriptions in US commercial claims data using a novel design. Using a large US commercial insurance database, we examined the completeness of warfarin prescription claims among patients with atrial fibrillation receiving regular medical follow-up and testing to manage warfarin dosing. We examined 14 different 6-month cross sections. Each cross section was treated independently to identify patients with at least two outpatient diagnoses of atrial fibrillation, two international normalized ratio tests, and one pharmacy claim. Trends in the percentage of patients with prescription claims for generic and branded warfarin were compared by year and 6-month periods using chi-square tests and generalized linear models adjusting for patient characteristics. Out of 111 170 patients, the percentage of patients with any warfarin drug decreased slightly from 91.7% (95% CI: 91.0, 92.4) in early 2003 to 87.1% (95% CI: 86.7-87.6) in late 2009 (χ(2) = 93.8, p < 0.0001). Over the same interval, the proportion of patients with generic warfarin exposure appearing increased significantly, whereas the proportion of patients with branded warfarin exposure decreased significantly. Our study supports the possibility that some prescriptions may not be captured in US commercial insurance databases.

Resource Use and Cost Implications of Switching Among Warfarin Formulations in Atrial Fibrillation Patients

Despite the uncertainty surrounding the safety of switching warfarin formulations, limited data exist on the resource use and costs associated with this switching pattern. To evaluate health care resource use and costs associated with switching warfarin formulations among patients with atrial fibrillation (AF) in a managed care organization. Patients diagnosed with AF (ICD-9 427.31) between July 2004 and August 2008 and who received warfarin therapy were identified in the HealthCore Integrated Research Database and categorized into 3 groups: users of generic warfarin formulations from a single drug manufacturer (generic-only group), users of branded warfarin formulations only (brand-only group), and patients who used generic and branded warfarin therapy interchangeably or who may have used generic drugs from 1 or more manufacturers (generic/brand switching group). Patients were followed 12 months or longer after their index warfarin prescription date to compare all-cause resource use and costs using multivariable regression analysis. The analysis included 12,908 patients: 71.82% were in the genericonly group, 9.61% were in the brand-only group, and 18.57% were in the generic/brand switching group. Patients in the generic/brand switching group were more likely to be hospitalized (relative risk [RR] = 1.43, p < 0.0001) or to use emergency department services (RR = 1.20, p < 0.01), compared to the brand-only users. Hospitalizations were more likely (RR = 1.26, p < 0.001) to occur among generic-only users versus brand-only users. Adjusted mean pharmacy costs per member per month were lower in the generic/brand switching group compared to the brand-only group ($257 vs $273, p = 0.038), but inpatient costs were higher ($1250 vs $972, p < 0.001), resulting in higher ($2125 vs $1847, p < 0.001) total costs. Generic-only users had lower pharmacy costs compared to brand-only users ($246 vs $273, p < 0.001), but total health care costs trended to be higher in the generic-only group ($1957 vs $1847, p = 0.053). The use of both generic and branded formulations of warfarin interchangeably, or the use of generics from more than 1 manufacturer, was associated with increased use of all-cause health care resources and total costs in patients with AF.

Hemorrhagic and Thrombotic Events Associated with Generic Substitution of Warfarin in Patients with Atrial Fibrillation: A Retrospective Analysis

Substitution of generic warfarin for imprint warfarin (Coumadin; DuPont/Bristol-Myers Squibb) has been a controversial issue due to bioavailability and bioequivalence concerns. To assess the risk of thrombotic and hemorrhagic events following substitution of warfarin formulations in patients with atrial fibrillation (AF). 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. 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. 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.

Brand Name versus Generic Warfarin: A Systematic Review of the Literature

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.

Improved Stability in INR with Coumadin for a Patient Requiring Very Low Warfarin Doses

Objective: To describe a patient who required very low doses of warfarin but who could not achieve therapeutically stable anticoagulation until treatment was switched from generic to branded warfarin. Case Summary: A 53-year-old male with a history of hypertension, coronary artery disease, heart failure, and mild renal insufficiency was diagnosed with atrial fibrillation during a routine examination. Anticoagulation was started with warfarin 5 mg daily. The patient presented to the anticoagulation clinic 2 days later with an international normalized ratio (INR) of 5.4 and no signs or symptoms of bleeding. Warfarin was held for 3 days until the INR was &lt;3. Warfarin was then restarted at 2.5 mg daily. Over the next week his INR rose to 4.8; warfarin was again held and restarted at 1.5 mg/day. Although the warfarin dose was eventually titrated to 6.5 mg/wk, the INR never stabilized and the patient only had consecutive therapeutic INRs twice in 1 year and only one 3-month period with therapeutic INRs not requiring any dosage adjustments. The decision was made to switch from the generic product to Coumadin to try to improve stability. Several dosage adjustments were made over the 6 weeks following the switch before the INR was stabilized with 7 mg/wk. Subsequent INRs ranged from 2.0 to 2.2 in the 3 months after the switch, during which time INRs were measured at least weekly. Over 14 months after the switch, the patient did not have an INR outside of the therapeutic range. Discussion: Many patients are able to take generic warfarin without problems. However, case reports have documented occasional patients who have had problems after switching to a generic product. Large cohorts have been switched to generic warfarin without experiencing significant changes in therapeutic control. However, 1 cohort study found that patients who required very low warfarin dosages had significant changes in their INR after switching to a generic product. Conclusions: Patients who require very low warfarin dosages to consistently maintain therapeutic anticoagulation may experience less therapeutic stability while on a generic product.

Clinical Consequences of Generic Warfarin Substitution: An Ecological Study

Clinical Consequences of Generic Warfarin Substitution: An Ecological Study