Biosimilars of low molecular weight heparins: Relevant background information for your drug formulary.

Biosimilars of low molecular weight heparins (LMWHs) are more alike the originator than different branded LMWHs. The latter differ largely in molecular weight, anti-FXa/anti-FIIa ratio and antithrombin binding. The Food and Drug Administration and European Medicines Agency guidelines are sufficient for the clinical use of high quality LMWHs. However, the Food and Drug Administration guideline lacks the results of a phase I clinical trial in the approval process. Most information about biosimilars is available for enoxaparin given that many biosimilars of enoxaparin have received market access. The guidelines of many International Thrombosis Societies for LMWH biosimilars are too stringent, not updated and impractical for formulary uptake discussions. This review gives background information on critical factors for the formulary uptake process of LMWHs with special attention for the use of the System of Objectified Judgment Analysis/Infomatrix model.

Extended-duration betrixaban versus shorter-duration enoxaparin for venous thromboembolism prophylaxis in critically ill medical patients: an APEX trial substudy.

PURPOSE: To assess the efficacy and safety of betrixaban for venous thromboembolism (VTE) prophylaxis among critically ill patients. METHODS: The APEX trial randomized 7513 acutely ill hospitalized patients to betrixaban for 35-42 days or enoxaparin for 10 ± 4 days. Among those, 703 critically ill patients admitted to the intensive care unit were included in the analysis, and 547 patients who had no severe renal insufficiency or P-glycoprotein inhibitor use were included in the full-dose stratum. The risk of VTE, bleeding, net clinical benefit (composite of VTE and major bleeding), and mortality was compared at 35-42 days and at 77 days. RESULTS: At 35-42 days, extended betrixaban reduced the risk of VTE (4.27% vs 7.95%, P = 0.042) without causing excess major bleeding (1.14% vs 3.13%, P = 0.07). Both VTE (3.32% vs 8.33%, P = 0.013) and major bleeding (0.00% vs 3.26%, P = 0.003) were decreased in the full-dose stratum. Patients who received betrixaban had more non-major bleeding than enoxaparin (overall population: 2.56% vs 0.28%, P = 0.011; full-dose stratum: 3.32% vs 0.36%, P = 0.010). Mortality was similar at the end of study (overall population: 13.39% vs 16.19%, P = 0.30; full-dose stratum: 13.65% vs 16.30%, P = 0.39). CONCLUSIONS: Compared with shorter-duration enoxaparin, critically ill medical patients who received extended-duration betrixaban had fewer VTE without more major bleeding events. The benefit of betrixaban was driven by preventing asymptomatic thrombosis and offset by an elevated risk of non-major bleeding. The APEX trial did not stratify by intensive care unit admission and the present study included a highly selected population of critically ill patients. These hypothesis-generating findings need to be validated in future studies. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

Revisión de dosieres de heparina y enoxaparina: Incumplimiento de la normativa de Costa Rica para el registro sanitario de biosimilares farmacéuticos / Heparin and enoxaparin dossiers review: Non-compliance of the Costa Rican regulation for the sanitary registration of pharmaceutical biosimilars

Objetivo: Determinar los aspectos esenciales de la reglamentación de Costa Rica referente al registro sanitario de biosimilares y compararlos con la información brindada en los dosieres de laboratorios fabricantes de heparina y enoxaparina. Materiales y métodos: Se examinó el Reglamento de Inscripción y Control de Medicamentos Biológicos: RTCR 440:2010. Luego, se solicitaron los dosieres enviados por los laboratorios fabricantes y se comparó su información con respecto a los datos solicitados por el reglamento anterior. Finalmente, se evaluó la importancia de la información solicitada. Resultados: El RTCR 440:2010 solicita información química, farmacéutica y biológica del producto farmacéutico terminado, resultados sobre seguridad y eficacia, datos administrativos y documentación legal. Para los biosimilares, se debe presentar el ejercicio de biosimilitud y un plan de farmacovigilancia. Esta información no está presente en su totalidad en los dosieres revisados. Conclusiones: Los productos revisados no cumplen con los requisitos solicitados por el reglamento costarricense en lo que respecta al ejercicio de biosimilitud. Por ende, no fueron presentados para el trámite de sus registros sanitarios ante el Ministerio de Salud de Costa Rica

Objective: To determine the essential aspects of the Costa Rican regulation concerning the sanitary registration of biosimilars and to compare them with the information provided in the dossiers of laboratories manufacturing heparin and enoxaparin. Methodology: The regulation for the Registration and Control of Biological Drugs: RTCR 440: 2010 was reviewed. Subsequently, the dossiers sent by the manufacturers were requested, and their information was compared with the data requested by the previous regulation. Finally, the importance of this information was evaluated. Results: The national regulations require chemical, pharmaceutical and biological information on the finished pharmaceutical product, results on safety and efficacy, administrative data and legal documentation. For biosimilars, the biosimilitude exercise and a pharmacovigilance plan must be presented. This information is not available in its entirety in the reviewed dossiers. Conclusions: The products reviewed do not meet the requirements of the Costa Rican regulations regarding the biosimilitude exercise. Therefore, they were not submitted for their drugs' applications before the Ministry of Health of Costa Rica

Comparison of Low-Molecular-Weight Heparins Prepared From Bovine Heparins With Enoxaparin.

Heparin and its low-molecular-weight heparin (LMWH) derivatives are widely used clinical anticoagulants. These drugs are critical for the practice of medicine in applications including kidney dialysis, cardiopulmonary bypass, and in the management of venous thromboembolism. Currently, these drugs are derived from livestock, primarily porcine intestine. The worldwide dependence on a single animal species has made the supply chain for this critical drug quite fragile, leading to the search for other sources of these drugs, including bovine tissues such as bovine intestine or lung. A number of laboratories are currently examining the similarities and differences between heparins prepared from porcine and bovine tissues. The current study is designed to compare LMWH prepared from bovine heparins through chemical ß-elimination, a process currently used to prepare the LMWH, enoxaparin, from porcine heparin. Using top-down, bottom-up, compositional analysis and bioassays, LMWHs, derived from bovine lung and intestine, are shown to closely resemble enoxaparin.

Differentiation of generic enoxaparins marketed in the United States by employing NMR and multivariate analysis.

The U.S. Food and Drug Administration defines criteria for the equivalence of Enoxaparin with Lovenox, comprising the equivalence of physiochemical properties, heparin source material and mode of depolymerization, disaccharide building blocks, fragment mapping and sequence of oligosaccharide species, biological and biochemical assays, and in vivo pharmacodynamic profile. Chemometric analysis of the NMR spectra, utilizing both (1)H and (1)H-(13)C HSQC NMR experiments, of Lovenox and Enoxaparin, the latter being the generic version of the former, revealed that Lovenox and the four Enoxaparin compounds produced by Sandoz (Enoxaparin and Fibrinox), Winthrop, and Amphastar exhibit dissimilarities in terms of their composition. All of the collected samples had expiry dates between 2012 and 2015. These studies, in addition to chromatographic analysis, highlighted signatures that differentiated the branded material from the generic products.

Reproducibility of the anti-Factor Xa and anti-Factor IIa assays applied to enoxaparin solution.

Enoxaparin is a widely used subcutaneously administered antithrombotic agent comprising a complex mixture of glycosaminoglycan chains. Owing to this complexity, its antithrombotic potency cannot be defined by physicochemical methods and is therefore evaluated using an enzymatic assay of anti-Xa and anti-IIa activity. Maintaining consistent anti-Xa activity in the final medicinal product allows physicians to ensure administration of the appropriate dosage to their patients. Bioassays are usually complex and display poorer reproducibility than physicochemical tests such as HPLC assays. Here, we describe the implementation of a common robotic platform and standard release potency testing procedures for enoxaparin sodium injection (Lovenox, Sanofi, Paris, France) products at seven quality control sites within Sanofi. Qualification and analytical procedures, as well as data handling, were optimized and harmonized to improve assay reproducibility. An inter-laboratory study was performed in routine-release conditions. The coefficients of variation for repeatability and reproducibility in assessments of anti-Xa activity were 1.0% and 1.2%, respectively. The tolerance interval in reproducibility precision conditions, expressed as percentage potency, was 96.8-103.2% of the drug product target of 10,000 IU/ml, comparing favorably with the United States of America Pharmacopeia specification (90-110%). The maximum difference between assays in two different laboratories is expected to be 4.1%. The reproducibility characteristics of anti-IIa activity assessments were found to be similar. These results demonstrate the effectiveness of the standardization process established and allow for further improvements to quality control in Lovenox manufacture. This process guarantees closeness between actual and target potencies, as exemplified by the results of release assays obtained during a three-year period.

Thromboelastographic evaluation of blood coagulation in the presence of branded and generic enoxaparins.

AIM: Enoxaparin is the most widely used low-molecular-weight heparin (LMWH) in the USA and has been approved for clinical use in multiple indications. Enoxaparin is a complex biological product with multiple known activities relevant to its antithrombotic effects, and variations in different forms of enoxaparin may have important clinical implications. This study aimed to compare the physiological anticoagulant activity of branded and a generic enoxaparin, using thromboelastography (TEG) to evaluate their effect on the dynamic formation of the blood clot as quantitated by interactions between coagulation factors and inhibitors, fibrinogen, platelets and the fibrinolytic system. METHODS: Whole native (no preservative) blood was obtained from 7 healthy volunteers. Samples were immediately mixed with various concentrations of branded or generic enoxaparin and TEG was performed to assess anticoagulant activity. Five different batches of each enoxaparin (branded and generic) were tested. RESULTS: Generic enoxaparin showed more variation in anticoagulation response with a less predictable concentration-dependent and linear response compared with branded enoxaparin. There was also an apparent batch-to-batch variation for generic enoxaparin. The results demonstrated a lower overall anticoagulant effect (P=0.05; no overlap of 95% confidence intervals) with a wider inter-individual variation for generic enoxaparin in comparison with branded enoxaparin. Some individuals responded with a higher than expected anticoagulant response to the given concentration of the generic enoxaparin. CONCLUSION: The findings of this study suggest that other pre-clinical and clinical studies should be done to validate the clinical interchangeability between branded and generic enoxaparin.

Propositional debate on biosimilar enoxaparin in Brazil.

Some patents of low-molecular-weight heparins (LMWHs) have expired and others are about to expire. Biosimilar versions of those drugs are available for clinical use in several countries. However, skepticism persists about the possibility of obtaining preparations similar to the original drug, because of the complexity of the process to generate LMWHs. In recent years, our laboratory has analyzed biosimilar samples of enoxaparin available for clinical use in Brazil (30 different batches and 70 finished products). Those preparations were assessed regarding their chemical structure, molecular weight distribution, in vitro anticoagulant activity, and pharmacological effects in animal models of thrombosis and bleeding. Our results have clearly shown that biosimilar preparations of enoxaparin are similar to the original drug. Our results have shown that those biosimilar versions of enoxaparin are a valid therapeutic alternative, which are, however, in need of appropriate regulation to ensure compliance with regulatory requirements.

Debate propositivo sobre os biossimilares de enoxaparina no Brasil / Propositional debate on biosimilar enoxaparin in Brazil / Debate de una propuesta sobre los biosimilares de enoxaparina en Brasil

Algumas patentes das heparinas de baixo peso molecular expiraram e outras estão vencendo. Versões biossimilares desses fármacos estão disponíveis para o uso clínico em vários países. Entretanto, ainda persiste ceticismo sobre a possibilidade de se obter preparações semelhantes ao medicamento original em razão do complexo processo para gerar heparina de baixo peso molecular. Nosso laboratório analisou, nos últimos anos, amostras de enoxaparina disponíveis para uso clínico no Brasil. Já analisamos 30 lotes distintos e 70 produtos acabados. Essas preparações foram avaliadas quanto à estrutura química, distribuição de peso molecular, atividade anticoagulante in vitro e efeitos farmacológicos em modelos animais de trombose e sangramento. Claramente, nossos resultados indicam que as preparações biossimilares de enoxaparina são semelhantes ao medicamento original. Nossos resultados indicam que essas versões biossimilares de enoxaparina são uma alternativa terapêutica válida, mas que requerem regulamentação adequada para assegurar o atendimento de requisitos regulatórios apropriados.

Some patents of low-molecular-weight heparins (LMWHs) have expired and others are about to expire. Biosimilar versions of those drugs are available for clinical use in several countries. However, skepticism persists about the possibility of obtaining preparations similar to the original drug, because of the complexity of the process to generate LMWHs. In recent years, our laboratory has analyzed biosimilar samples of enoxaparin available for clinical use in Brazil (30 different batches and 70 finished products). Those preparations were assessed regarding their chemical structure, molecular weight distribution, in vitro anticoagulant activity, and pharmacological effects in animal models of thrombosis and bleeding. Our results have clearly shown that biosimilar preparations of enoxaparin are similar to the original drug. Our results have shown that those biosimilar versions of enoxaparin are a valid therapeutic alternative, which are, however, in need of appropriate regulation to ensure compliance with regulatory requirements.

Algunas patentes de las heparinas de bajo peso molecular caducaron y otras van por el mismo camino. Versiones biosimilares de esos fármacos están disponibles para el uso clínico en varios países. Sin embargo, todavía persiste el escepticismo sobre la posibilidad de obtener preparaciones similares al medicamento original en razón del complejo proceso para producir la heparina de bajo peso molecular. En los últimos años, nuestro laboratorio analizó muestras de enoxaparina disponibles para el uso clínico en Brasil. Ya hemos analizado 30 lotes distintos y 70 productos acabados. Esas preparaciones fueron evaluadas en cuanto a la estructura química, distribución de peso molecular, actividad anticoagulante in vitro y efectos farmacológicos en modelos animales de trombosis y sangramiento. Lógicamente que nuestros resultados indican que las preparaciones biosimilares de enoxaparina son similares al medicamento original. Nuestros resultados dan fe de que esas versiones biosimilares de enoxaparina son una alternativa terapéutica válida, pero que requieren una reglamentación adecuada para garantizar la atención de los requisitos reglamentarios pertinentes.

Cost comparison of tinzaparin versus enoxaparin as deep venous thrombosis prophylaxis in spinal cord injury: preliminary data.

Thromboembolic events are major causes of morbidity and mortality in patients with spinal cord injuries. Low molecular weight heparins are recommended as prophylaxis against such events. The purpose of the current study was to perform a cost analysis of tinzaparin versus enoxaparin using published efficacy and safety data as deep vein thrombosis and pulmonary embolism prophylaxis in this population. All published English language articles evaluating either tinzaparin or enoxaparin as pharmacoprophylaxis in spinal cord-injured patients were identified. Data from these studies were subjected to cost-effectiveness analyses followed by sensitivity analyses to determine which agent is the most cost-effective in these patients. Results demonstrated that tinzaparin 3500 U daily and enoxaparin 30 mg every 12 h are both cost-effective agents for thromboembolism prophylaxis in patients with spinal cord injuries.

Benefits of deep-vein thrombosis prophylaxis in the nonsurgical patient: The MEDENOX trial.

Venous thromboembolism (VTE) is a common complication of hospitalized patients, imposing a major clinical and economic burden. Three of four cases of fatal pulmonary embolism occur in nonsurgical settings, but thromboprophylaxis is far less common in medical than in surgical patients. This is mainly attributable to the heterogeneity of nonsurgical populations and lack of high-quality evidence to support specific thromboprophylactic measures. The recent Prophylaxis of Venous Thromboembolism in MEDical Patients With ENOXaparin (MEDENOX) trial addressed this deficiency by assessing the need for and the benefit:risk ratio of thromboprophylaxis in a well-defined group of medical patients immobilized with severe illness. The MEDENOX study showed that these patients are at significant risk of VTE. Enoxaparin, 40 mg once daily for 6 to 14 days, reduced the risk of VTE by 63% without increasing adverse events. It is anticipated that data from the MEDENOX study will be incorporated into future consensus guidelines on the prevention of VTE. Further studies are required to assess the benefit:risk ratio of therapy in other clearly-defined medical groups.

Superiority of enoxaparin over heparin in combination with a GPIIb/IIIa receptor antagonist during coronary thrombolysis in dogs.

It is known that a low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin in unstable angina/non-Q-wave myocardial infarction (UA/NQMI) and the platelet GPIIb/IIIa receptors play an important role in acute myocardial infarction (AMI). Therefore, enoxaparin might have a similar advantage over heparin when used with a GPIIb/IIIa antagonist (RPR109891) in coronary thrombolysis. After induction of coronary thrombosis in anesthetized dogs, infusion of saline, enoxaparin, heparin, RPR109891, enoxaparin+RPR109891, or heparin+RPR109891 was initiated followed 15 min later by recombinant tissue plasminogen activator (rt-PA). The incidence of reperfusion in the enoxaparin+RPR109891- and the heparin+RPR109891-treated groups was similar, but time to reperfusion tended to be shorter for enoxaparin versus heparin. Only 43% of the vessels reoccluded in the enoxaparin+RPR109891 group, compared to 100% vessels in the heparin+RPR109891 group. Enoxaparin+RPR109891 maintained flow for a significantly longer time compared to saline, enoxaparin, heparin, and heparin+RPR109891. Enoxaparin+RPR109891 and heparin+RPR109891 increased the template bleeding time by 2- and 3-fold and activated partial thromboplastin time (APTT) by 1.3- and 3-fold, respectively. These data suggest that enoxaparin is more effective and potentially safer than heparin when combined with a GPIIb/IIIa receptor antagonist during rt-PA-induced coronary thrombolysis.

The TETAMI trial: the safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and of tirofiban versus placebo in the treatment of acute myocardial infarction for patients not thrombolyzed: methods and design.

Patients with acute myocardial infarction (AMI) who do not receive early reperfusion therapy are at high risk of reinfarction or death, and the efficacy and safety of antithrombotic therapy in this group of patients has not been evaluated. Enoxaparin is a low-molecular-weight heparin (LMWH) that has previously been shown to reduce the incidence of ischemic events in patients with unstable angina or non-Q-wave MI. The principal aims of the TETAMI study are to investigate the efficacy and safety of treatment with enoxaparin or tirofiban (a glycoprotein IIb/IIIa receptor antagonist) alone or in combination for 2 to 8 days in patients with AMI who are not eligible for early reperfusion therapy. In this 2 by 2 factorial design study approximately 900 patients will be randomly assigned, in a blinded manner, to one of four treatments: enoxaparin alone, enoxaparin plus tirofiban, unfractionated heparin (UFH), or UFH plus tirofiban, with appropriate matched placebos. The primary end point is the composite of death, recurrent AMI, and recurrent angina, analyzed at 30 days after AMI. The design and methods of the TETAMI study are described in this article.

Anti-thrombotic efficacies of enoxaparin, dalteparin, and unfractionated heparin in venous thrombo-embolism.

BACKGROUND: Few data exist by which the anti-thrombotic efficacy of different anticoagulants may be compared. We used a radiolabeled antibody specific for polymerizing fibrin to compare the in vivo anti-thrombotic potencies of different systemic anticoagulants (enoxaparin, dalteparin, and unfractionated heparin). METHODS AND RESULTS: Deep venous thrombi (DVTs) were induced in dogs' femoral veins. The dogs were then treated with one of the following subcutaneous regimens: enoxaparin 100 units/kg (1.0 mg/kg) every 12 hours (n=4), dalteparin 200 units/kg every 24 hours (n=4), or unfractionated heparin 240 units/kg every 8 hours with dose adjustment via aPTT (n=3). 111Indium-labeled anti-fibrin antibodies, specific for propagating thrombi, were given intravenously and nuclear scans of the legs were taken over the following 24 hours. Thrombus propagation was estimated by the ratio of gamma emissions from the legs containing DVTs divided by the emissions from the contralateral "control" legs. DVTs accumulated labeled anti-fibrin antibodies at the same rates in both the enoxaparin group and the dalteparin group (gamma emissions 171+/-6% and 168+/-36% of control by 24 hours, respectively). DVTs in the adjusted dose unfractionated heparin group tended to accumulate antibodies at a slower rate (129+/-19% of control by 24 hours). CONCLUSIONS: Enoxaparin and dalteparin inhibited propagation of pre-formed thrombi to the same degree. Subcutaneous unfractionated heparin, adjusted every 8 hours by aPTT, tended to suppress ongoing thrombosis more than either LMWH.

Comparing the antithrombotic efficacy of a humanized anti-factor IX(a) monoclonal antibody (SB 249417) to the low molecular weight heparin enoxaparin in a rat model of arterial thrombosis.

A humanized inhibitory anti-factor IX(a) antibody (SB 249417) has been compared to enoxaparin (Lovenox) in a rat model of arterial thrombosis. Pretreatment of rats with either SB 249417 (3.0 mg/kg, i. v.) or enoxaparin (30.0 mg/kg, i.v. or s.c.) resulted in comparable and significant reductions in thrombus formation. However, the efficacious dose of enoxaparin resulted in >30-fold increase in the aPTT over baseline, while the efficacious dose of SB 249417 prolonged the aPTT by only approximately 3-fold. Additionally, pretreatment with SB 249417 resulted in sustained blood flow and arterial patency throughout the experiment in >80% of rats treated. In contrast, <30% of rats pretreated with enoxaparin remained patent throughout the experiment. The data in this report indicate that the selective inhibition of factor IX(a) with the monoclonal antibody SB 249417 produces a superior antithrombotic profile to that of the low molecular weight heparin enoxaparin.

An equivalence study of two low-molecular-weight heparins in the prevention and treatment of deep-vein thrombosis after total hip replacement.

Low-molecular-weight heparins have been evaluated against unfractionated heparin and have been shown to have clinical benefits in the perioperative setting during orthopedic surgery. Two low-molecular-weight heparins, tinzaparin and enoxaparin, were assessed for equivalency in efficacy and safety in 499 patients undergoing elective hip replacement. The two anticoagulants were found to be effective and safe in this setting in the specified patient type. No statistical difference was observed in the incidence of bleeding. Clinical side effects tended to be greater in patients with a higher body mass index, which could serve as a possible indicator for the risk of deep vein thrombosis.