Generic Enoxaparin Research Articles

Skin necrosis induced by generic enoxaparin

Skin necrosis induced by generic enoxaparin

More is Less: Extended Enoxaparin After Surgery for Inflammatory Bowel Disease - A Cost-based Decision-Analysis

Inflammatory Bowel Disease (IBD) patients undergoing colorectal surgery are at an increased risk of Venous Thromboembolism (VTE), particularly beyond 10 days post-op. Optimal VTE prophylaxis, however, is not well defined in this population. In cancer patients undergoing abdominopelvic surgery, several randomized trials suggested that extended therapy with enoxaparin was a more effective treatment strategy, while several decision analyses suggested subcutaneous heparin may result in more cost minimization. These previous studies were performed prior to the availability of generic enoxaparin and failed to incorporate rates of patient compliance. Thus we aimed to construct a cost minimization decision analysis which included these important factors in a population known to be at high-risk for VTE. We constructed a cost minimization decision model to evaluate four strategies for management of postoperative VTE risk after surgery for IBD: (1) inpatient subcutaneous heparin (SQH) 5000 units TID × 10 days; (2) inpatient enoxaparin 40 mg daily × 10 days; (3) SQH 5000 units TID × 30 total days (10 inpatient, 20 outpatient days); (4) enoxaparin 40 mg daily × 30 total days (10 inpatient, 20 outpatient days). Our model made the following assumptions: (1) no prior history of VTE; (2) only major bleeding required intervention; (3) 90% of major bleeds were treated medically with transfusion of 2 units PRBC and 10% required reoperation; (4) heparin-induced thrombocytopenia (HIT) occurred within the first 10 days of exposure. Rates of inpatient and outpatient VTE, adherence to outpatient treatment, and strategy specific complications including HIT and major bleeding for each strategy, were obtained from published literature and modeled. Costs (in US dollars), including costs of strategy specific complications, were based on published literature, institutional charges and average wholesale pricing. Sensitivity analyses were performed to account for uncertainty in estimates. In this model, extended duration prophylaxis with enoxaparin was associated with the greatest cost minimization with an estimated cost of $2,585, compared to extended SQH which cost $2,768. Inpatient-only prophylaxis with enoxaparin and SQH cost $2,944 and $3,267, respectively. Our model was sensitive to rates of VTE (Figure 1), rates of HIT, and drug costs (Figure 2). Sensitivity analysis revealed that the extended SQH strategy was associated with the most cost minimization when VTE rates with enoxaparin were >6.5% (vs. 5.7% in the base case) and costs of outpatient enoxaparin were >$712 (vs. $528 in the base case). SQH was also associated with the most cost minimization if patient adherence rates were >85% (vs. 65% in the base case). Our model, in contrast to previously published cancer surgery literature, suggests that in IBD patients extended duration prophylaxis with enoxaparin for a total of 30 days post-operatively would result in the greatest costminimization. This may be in part due to the availability of generic enoxaparin, reduced risk of HIT, and increased adherence with outpatient enoxaparin resulting in greater VTE prevention relative to SQH.

Comparative Studies On Branded Enoxaparin and a US Generic Version of Enoxaparin.

Abstract 2264 Background:Low molecular weight heparins (LMWHs) are complex biologic drugs whose heterogeneity in saccharide chain length and in the composition (sulfate, acetyl), content, and location of functional groups can impact their multiple biologic activities. Enoxaparin (Lovenox®) is validated for multiple indications and is the most widely used LMWH in the US. Several generic versions of enoxaparin are currently available in the US. We undertook this study to compare the activity profile of branded and a generic enoxaparin. Methods:Five batches each of branded (B; Sanofi-aventis; Bridgewater, NJ) and generic (G; Sandoz US; Princeton, NJ) enoxaparin were studied. Drugs were purchased through hospital pharmacies as pre-filled syringes containing 40 mg drug. The molecular weight profile of each batch of LMWH was determined using HPLC. To analyze in vitro activities, LMWHs were supplemented to normal human plasma and assessed using amidolytic anti-FXa and anti-FIIa, fibrinokinetic, and thrombin generation assays. Human whole blood was supplemented with LMWHs and the dynamic blood coagulation process was analyzed by thrombelastography (TEG). Whole blood flow cytometry was used to assess the ability of the LMWHs to inhibit tissue factor (TF)-induced platelet activation and lipopolysaccharide (LPS)-induced neutrophil activation. To assess the in vivo effect of the LMWHs, primates treated subcutaneously with a dose of 1 mg/kg LMWH had blood samples drawn pre-treatment and at 4, 6, 12 and 24 hours. Ex vivo pharmacodynamic activities of TFPI release, TAFI inhibition, and thrombin generation inhibition were evaluated. Results:Molecular weight parameters and IC50 values for FXa and FIIa inhibition by branded and generic enoxaparin were comparable. In the in vitro thrombin generation and fibrinokinetic assays, branded enoxaparin exhibited a more potent anticoagulant effect demonstrating slower clot formation with a weaker final clot structure (p=0.01) than generic enoxaparin. Although both the branded and generic enoxaparin produced a concentration-dependent anticoagulant effect in the TEG, there was greater degree of variability for the generic product between blood donors and between batches resulting in a less predictable linear response as drug concentration increased. When the increase in TEG R-time was plotted vs. concentration, branded enoxaparin showed a stronger anticoagulant effect (p=0.05). A concentration-dependent reduction in TF-induced platelet P-selectin expression was observed with branded and generic enoxaparin producing a similar effect. Incubation of whole blood with LPS resulted in a dramatic increase in neutrophil CD11b expression (MFI: 13.1±2.8 vs. 249.0±42.1) which was reduced by increasing concentrations of LMWH. This effect appeared to be stronger for generic than branded enoxaparin (MFI: 165.2±31.9 vs. 208.9±25.9). In primates treated with branded and generic enoxaparin, anti-FXa activity assessed by AUC 0–24hrs was similar. Anti-FIIa activity, however, was significantly higher in primates treated with generic enoxaparin (135±28 vs. 91±20 (μg*hr)/ml; p=0.023). AUC for thrombin generation inhibition was (B) 932±59 vs. (G) 775±119 %inhibition*hr; p=0.029. AUC for TFPI release was (B) 1101±98 vs. (G) 822±13 (ng/*hr)/ml; p=0.006. AUC for inhibition of TAFI activation was (B) 780±73 vs. 906±69 % inhibition*hr; p=0.023. Conclusions:This investigation demonstrated a wider variation in anticoagulant response to generic enoxaparin in comparison to branded enoxaparin. This variation was due to the response of the individual subject as well as to the batch of the product. In addition, both in vitro and in vivo/ex vivo activity differences were observed between branded and generic enoxaparin in several parameters relevant to the antithrombotic effect of LMWH. These findings suggest that simple analytical characterization can establish good quality control in manufacturing but may not assure similarity in biological performance between branded and generic enoxaparin. Thus beside the routinely required characterization, inclusion of additional tests for biologic activities and pharmacodynamic profiling of generic products in animal models may provide useful information on the bioequivalence of the generic versions of enoxaparin. Disclosures:Walenga:Sanofi-Aventis, Paris, France: Research Funding. Jeske:Sanofi-Aventis, Paris, France: Research Funding. Hoppensteadt:Sanofi-Aventis, Paris, France: Research Funding. Cunanan:Sanofi-Aventis, Paris, France: Research Funding. Escalante:Sanofi-Aventis, Paris, France: Research Funding. Khan:Sanofi-Aventis, Paris, France: Research Funding. Bailey:Sanofi-Aventis, Paris, France: Research Funding. Fareed:Sanofi-Aventis, Paris, France: Research Funding. Bakhos:Sanofi-Aventis, Paris, France: Research Funding.

Comparative Antithrombotic and Bleeding Effects of Two U.S. Generic Enoxaparins

Abstract 1172 Background:Low molecular weight heparins (LMWHs) are complex biologic drugs that exhibit heterogeneity in terms of saccharide chain length and in the composition (sulfate, acetyl), content, and location of functional groups. Such heterogeneity impacts the biologic activity of LMWHs as there is a certain threshold chain length required for thrombin inhibitory activity and a particular sequence is required for interaction with antithrombin. In July 2010 the US Food and Drug Administration published requirements necessary to demonstrate the ‘sameness' of generic LMWHs with the originator LMWH. We undertook this study to compare the primary anticoagulant effect of thrombosis prevention and the primary adverse effect of bleeding of two FDA approved generic enoxaparins. Methods:Four batches of commercially available Sandoz US generic enoxaparin (Princeton, NJ) and two batches of Watson US generic enoxaparin (Parsippany, NJ) were compared. All products were obtained from hospital pharmacies as pre-filled syringes containing 40 mg of the drugs. The molecular weight profile of each batch was determined by HPLC in relation to well-defined heparin fractions and by utilizing the US Pharmacopeia method. In vitro activity was determined by supplementing each LMWH batch to normal human plasma over a range of concentrations (0–10 mg/ml) and analyzing these samples using aPTT, anti-FXa and anti-FIIa assays. Hemorrhagic activity was measured using a rat tail transection model five minutes after administration of a 2 mg/kg intravenous dose (n=8 rats/batch). Upon completion of the bleeding model, antithrombotic activity was assessed using a jugular vein clamping model (∼90 minutes post-dosing). Blood samples collected from treated rats were used to estimate circulating blood levels of LMWH using anti-FXa and anti-FIIa assays. Results:The two groups of generic enoxaparins exhibited a similar molecular weight profile with mean molecular weights of 4,270 ± 20 Da for the Sandoz products and 4,420 ± 80 Da for the Watson products. In vitro activities were similar between batches of the same product, but the individual products differed considerably (p=0.01). In the aPTT and anti-FIIa assays, the Watson LMWH produced significantly more activity than the Sandoz LMWH at concentrations ≥5 μg/ml. At 5 μg/ml, a clotting time of 74.0 ± 16.6 sec was observed with Watson batches compared to clotting times ranging from 52.9 to 54.9 sec for Sandoz LMWHs. While a similar pattern was observed with the anti-FXa assay, the differences between products were not statistically significant. In the bleeding model, all LMWHs prolonged the bleeding time compared to vehicle control. One batch of the Watson LMWH, however, produced a significantly longer bleeding time compared to all other samples tested (33.8 ± 5.1 min vs. a range of 11.9 ± 2.4 to 18.3 ± 4.3 minutes for the other samples; p=0.003). The same batch produced significantly more antithrombotic activity (6.3 ± 0.7 clampings) compared to the other samples (range of 4.0 ± 0.6 to 4.6 ± 0.5 clampings; p<0.001). One batch of Sandoz LMWH produced a significantly smaller prolongation of bleeding time compared to other samples. Circulating drug levels determined by anti-FXa and anti-FIIa activities were comparable in all treatment groups but did not appear to correlate with hemorrhagic or antithrombotic activities. Conclusion:The expectation was that all batches of all generic enoxaparins would produce the same in vitro, in vivo, and ex vivo outcomes. The findings of this study suggest that incorporation of traditional animal models in the development of generic enoxaparins may be of value as multiple biological effects of LMWHs, not fully addressed with the anti-FXa and anti-FIIa activities, contribute to the overall antithrombotic activity of these LMWHs. This study demonstrates that all generic enoxaparins available today may not necessarily be the same. These findings underscore the importance of in vivo studies in animal models to demonstrate the bioequivalence of the generic products. Disclosures:Jeske:Sanofi-Aventis, Paris, France: Research Funding. Walenga:Sanofi-Aventis, Paris, France: Research Funding. Escalante:Sanofi-Aventis, Paris, France: Research Funding. Hoppensteadt:Sanofi-Aventis, Paris, France: Research Funding. Cunanan:Sanofi-Aventis, Paris, France: Research Funding. Kahn:Sanofi-Aventis, Paris, France: Research Funding. Paulus:Sanofi-Aventis, Paris, France: Research Funding. Fareed:Sanofi-Aventis, Paris, France: Research Funding. Bakhos:Sanofi-Aventis, Paris, France: Research Funding.

Comparative Studies on Branded Enoxaparin and a US Generic Version of Enoxaparin

Enoxaparin, a complex, biologically derived low-molecular-weight heparin, is approved for a range of clinical indications. This study was carried out to compare the potency profile and pharmacodynamic responses of branded enoxaparin (Lovenox; Sanofi, US) with a generic enoxaparin (enoxaparin sodium injection, USP). Five batches of each product were tested. Although the average molecular weight, anti-factor Xa, and anti-factor IIa potencies were similar for the two products, differences were observed in the in vitro thrombin generation and kinetics of clot formation (P = .01) and in the ex vivo pharmacodynamics regarding thrombin generation inhibition (P = .029), tissue factor pathway inhibitor release (P = .006), and inhibition of the active form of thrombin-activated fibrinolysis inhibitor (P = .023). These findings suggest that simple analytical characterization can establish good quality control in manufacturing, but they may not assure similarity in biological performance between the branded and the generic enoxaparin.

The development and introduction of biosimilar anticoagulants &amp;ndash; focus on enoxaparin

The aims of this paper are to discuss the: (1) pharmacology of low-molecular-weight heparins (LMWHs) emphasizing their synthesis, mechanism of action, and comparison with the compound, unfractionated heparin (UFH); and (2) recent controversial approval by the Food and Drug Administration (FDA) of a generic enoxaparin. Enoxaparin is one of several LMWHs that are currently available worldwide for clinical use. LMWHs are derived by chemi- cal or enzymatic depolymerization of the parent molecule, UFH. Both UFH and LMWHs exert their primary antithrombotic effect by binding to and catalyzing the naturally-occurring anticoagulant, antithrombin. LMWHs are more effective at inhibiting factor Xa than factor IIa (thrombin). They also produce less heparin-induced thrombocytopenia and osteoporosis than UFH and are at least as effective and safe as UFH for each approved indication. They are safe and effective when given subcutaneously once or twice daily, without the need for anticoagulant monitoring, and are suitable for out-of-hospital treatment. The FDA first approved enoxaparin (Lovenox ®

Patient cost associated with filling a prescription for extended-duration venous thromboembolism (VTE) prophylaxis following surgery for gynecologic cancer

ObjectiveThe primary purpose of this study was to determine the average patient cost for filling a prescription for extended-duration enoxaparin prophylaxis. MethodsWomen who underwent major abdominal/pelvic surgery for histologically confirmed gynecologic malignancy were included. Patients who underwent minimally invasive surgery, had benign disease or were on treatment for existing VTE were excluded. Pharmacy resource specialists electronically submitted test prescriptions to verify enoxaparin coverage in the outpatient setting prior to hospital discharge. Patient co-pay information collected included: the number of patients requiring prescription insurance prior authorization, those qualifying for the Lovenox Patient Assistance Program® (PAP) and insurance status. ResultsThree hundred and sixty-four patients were discharged with extended-duration enoxaparin prophylaxis for 28days between October 2009 and May 2011. The average patient cost to complete 28days of enoxaparin prophylaxis was $62 (median $21, range $0–1210). Prior authorization was required for 32 patients (10%). Two patients (0.6%) qualified for the Lovenox Patient Assistance Program®. A decrease in the average patient cost from $71 to $52 (median $30 to $10) was observed after generic enoxaparin approval in July 2011. ConclusionOur results show that at least 90% of patients filled their prescription of extended-duration enoxaparin prophylaxis after major abdominal surgery for cancer regardless of cost.

Despite Pharmaceutical Equivalence, Generic Versions of Enoxaparin May Differ in Their Pharmacodynamic Actions. Potential Clinical Implications

IntroductionThis study compared available generic enoxaparins with the branded version (Sanofi‐Aventis) in various assays and investigated their pharmacokinetic/pharmacodynamic behavior in a primate model.MethodsCutenox, Lupenox, enoxaparin Sandoz and Lovenox were compared in terms of molecular weight profiling, NMR profile and in vitro anticoagulant activity. Groups of primates (n=8–10) were administered LMWH (1 mg/kg subcutaneously) and blood samples were drawn over a 24 hour period to measure pharmacodynamic effects. Antithrombotic and bleeding effects were studied in rat models of jugular vein clamping and tail transection, respectively. Complexation studies with PF4 were carried out using a SELDI‐MS method.ResultsAnti‐Xa potency ranged from 86–110 U/mg and anti‐IIa potency ranged from 27–35 U/mg. Mean molecular weight of these LMWHs ranged from 4.2–4.5 kDa. Despite comparable pharmaceutical profiles, some of these products showed differences in the pharmacodynamic effects in terms of TFPI release, TAFI modulation, thrombin generation inhibition and protamine neutralization.ConclusionAlthough the generic enoxaparins are pharmaceutically equivalent, their pharmacodynamic profiles differ from the branded product. Thus, each generic product should be considered as a distinct LMWH and individual safety/efficacy data should be considered prior to its clinical use.

Structural and Pharmacological Profile of Generic Enoxaparins Used in Brazil

Generic active pharmaceutical ingredients (APIs) have been commonly used in Brazil, since 1999, but most of them are synthetic and small molecules. Recently, a large number of generic enoxaparins were introduced into the market raising concerns related to product-to-product interchangeability, efficiency, and drug counterfeiting. These drugs are produced from biological sources and their production involves complex procedures and purification processes. The present article evaluates several generic enoxaparins, structurally and pharmacologically, and compares them with the branded products. Structural analysis showed that the generic products are, indeed, quite similar to the branded products, however, this similarity cannot be extended to their pharmacological activities. The results showed that generic products must go through extensive structural, pharmacological, and clinical evaluation in order to assess their quality, efficacy and, ultimately, avoid drug counterfeiting before clinical use. Variation was also observed between the branded products, showing that such drugs must be at constant surveillance.

Product Associated Variation in Generic Enoxaparin. Potential Clinical Implications

Abstract 1249Recently the generic versions of enoxaparin brand (Sanofi-Aventis) have widely become available. Since enoxaparin is a biological product, minor compositional changes in these agents may potentially have clinical implications. Generic enoxaparins are manufactured by several companies and marketed under specific trade names. The purpose of this investigation was to determine the differences between generic products and within product variations in the same generic product. Eight generic products from India (Cutenox, Markaparin,Clenox, Lomoparin, Lupenox, Lomorin-NX, Lomoh-40 and Troynoxa-40), four generic products from South America (Enoxalow, Versa, Heptron and Endocris), and one generic product from the USA (Enoxaparin sodium) were studied. The molecular weight profile of generic products showed relatively similar distribution profile with a molecular weight range of 3.9–4.9 kDa. The anti-FXa activity ranged from 87–110 U/mg, whereas wider variations were noted in anti-FIIa activity (28–41 U/mg). The anti-FXa:anti-FIIa ratio ranged from 3.1–4.2. Much wider variations (up to 60%) were noted in the anticoagulant assays (ACT, aPTT, Heptest, and thrombin time). Additionally the generic products also showed variations in the thrombin generation assay. Protamine and PF4 titration profile also showed variations. AT mediated inhibition of thrombin and FXa in the biochemical assays showed wider differences in IC50 values. Heparinase digestion profile showed variable oligosaccharide composition and some of the products contained heparinase resistant glycosaminoglycans. A comparison of 5 batches of the branded enoxaparin (Clexane) and 5 batches of a generic enoxaparin showed that the generic product batches exhibited greater variation in the biologic assays despite a comparable anti-FXa profile. These observations suggest that despite the current regulatory requirements, product based differences in the generic enoxaparins exist, which may impact their safety and efficacy profile in cardiovascular and thrombotic indications for which the branded enoxaparin is approved. Additional pharmacodynamic studies and clinical validations of the safety and efficacy of each of the generic products maybe helpful in assuring a clinical equivalence of the generic products with the branded enoxaparin. Disclosures:No relevant conflicts of interest to declare.

Comparison of the Pharmacokinetic and Pharmacodynamic Behavior of Branded and Generic Enoxaparin in Non-Human Primates

Abstract 1254 Introduction:Low molecular weight heparins (LMWHs) have been shown to be safe and effective in the prevention and treatment of venous thrombosis and in the treatment of patients with pulmonary embolism or acute coronary syndrome. Commercially available LMWHs are distinct agents in terms of their molecular weight profile and in vitro potency. Molecular weight influences the pharmacokinetics (PK) and pharmacodynamics (PD) of heparin oligosaccharides. Although there continues to be interest in developing biosimilar versions of LMWHs, defining biosimilarity for LMWHs is challenging because chemical means of measuring plasma heparin levels do not exist, potency measures typically only measure AT-dependent activities, bioequivalence in terms of one activity does not ensure identical pharmacokinetic behavior in terms of other biological activities and identification and quantification of the various oligosaccharide components in a LMWH preparation is difficult. In vitro studies have shown that biosimilar LMWHs can differ considerably from the branded product as well as from each other. In the current study, the PD behavior of branded and biosimilar enoxaparin was compared in a cross-over study following a single subcutaneous dose to non-human primates. Methods:Lovenox (lot #514956, sanofi-aventis, Paris, France) and Fibrinox (lot#0002, Sandoz S.A., Buenos Aires, Argentina) were obtained in pre-filled syringes at a concentration of 100 mg/ml. Upon anesthesia, the non-human primates (Macaca mulatta) were weighed and a baseline blood sample was collected. A site on the abdomen was shaved and cleansed prior to the subcutaneous administration of LMWH. Blood samples were collected at 1, 4, 6 and 28 hours post-administration and were centrifuged to make platelet poor plasma which was stored in aliquots at −70°C until analysis. Primates were randomly dosed with one of the two test agents. After a minimum of one week wash-out, the same primates were dosed with the other test agent. Plasma samples were evaluated using clot-based and amidolytic assays. LMWH concentrations in the blood samples were determined by extrapolation from in vitro concentration-response curves and used to calculate values for PK parameters. p-values < 0.05 determined by two-way repeated measures analysis of variance were considered to be statistically significant. Results:LMWH levels determined by circulating anti-Xa activity following Fibrinox and Lovenox administration were not observed to be significantly different. Circulating anti-IIa levels, however, were significantly higher in Lovenox-treated animals at 1, 4 and 6 hours post-administration. Using the Heptest assay, higher circulating drug levels were measured in Fibrinox-treated animals at 4 and 6 hours. A high degree of variability was observed in the absorption and elimination of the LMWHs. Statistically significant differences in pharmacokinetic behavior was not observed when circulating drug concentrations were determined using anti-Xa activity or Heptest prolongation. Using drug concentrations determined from anti-IIa activity, the AUC following Lovenox treatment was significantly larger than following Fibrinox treatment. Plotting mean drug levels based on anti-IIa activity versus mean drug levels based on anti-Xa activity at the various sample times indicated a hysteretic relationship which was distinct for Fibrinox and Lovenox-treated primates. Clear differentiation of the two LMWHs was also observed when drug levels measured by anti-IIa activity were plotted against those determined using the prolongation of the Heptest. Conclusions:Potency of LMWHs can be expressed in terms of a number of AT-dependent and AT-independent activities, which may not be proportional. The PK/PD behavior of LMWHs is different when drug levels are determined using distinct biologic activities. The measured concentration of a drug and its corresponding effect can be asynchronous, that is, peak drug levels may not occur at the same time as peak effect levels. In this study, plotting drug concentrations determined by one functional parameter against those derived from a different parameter provided clear visual evidence that the two LMWHs tested exhibit distinct pharmacodynamic behavior. In vivo behavior is an important consideration for defining pharmacoequivalence of complex biologic drugs. Disclosures:No relevant conflicts of interest to declare.

Should Generic Versions of Low Molecular Weight Heparins Be Considered As Generic or Biosimilar Drugs. A Regulatory Dilemma

Abstract 4328The patent protections for the low molecular weight heparin (LMWHs) enoxaparin, dalteparin and tinzaparin have expired and their generic respective versions are available. Despite widespread clinical use the global regulatory pathways to develop and approve these products remain unclear. In South America and Southeast Asia generic versions of LMWHs are available without adequate regulatory oversight. The EMEA has considered these agents as biosimilars and require both pharmaceutical and clinical data for approval. Unlike the EMEA, the US FDA requires data on the basic, chemical, and pharmacologic profiles without any clinical validation. In July 2010, the FDA approved a generic version of enoxaparin for all of the clinical indications for which the branded enoxaparin is approved. On the other hand, Initially the FDA had approved the different branded LMWHs as distinct drug entities, requiring clinical trials for each individual clinical indication. Generic enoxaparins from various manufacturers are marketed under different trade names even when they are manufactured by the same company. Although in the pharmacopeial assays these agents exhibit comparability, in the pharmacodynamic studies assay based differences have been reported. In a study conducted on two batches of Sandoz's enoxaparin and Lovenox®, while no differences were noted in the molecular profile and anti-FXa activity, significant differences were noted in other assays such as thrombin generation inhibition and PF4 titration. Moreover, pharmacodynamic differences in primates after sc administration were also noted which were more obvious in the release of tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor assays (TAFI).As the manufacturing process of these agents may differ from manufacturer to manufacturer it is likely that certain compositional variations are not detectable by chemical methods. Thus the requirement of clinical trials to assure the safety and efficacy of these agents is an important consideration. Of concern is the disharmonization of pathways between different regulatory bodies which contribute to the complexity of this issue. It is proposed that the EMEA, FDA and other regulatory bodies develop some common global guidelines for the rationale development of these drugs. Disclosures:No relevant conflicts of interest to declare.

Pharmacodynamic Differences in the Two Generic Brands of Enoxaparin

Abstract 1251Several generic versions of enoxaparin have recently become available. While these generic versions of enoxaparin exhibit similar molecular profiles and comparable anti-Xa activities; product specific differences in global anticoagulant (APTT, Heptest and thrombin generation inhibition) have been reported. The purpose of this study was to compare a generic version of enoxaparin Sandoz from Argentina (Fibrinox lot 002) and from the US (enoxaparin lot 914786) in various in vitro whole blood and plasma based clotting tests. Despite comparable molecular profile and anti-Xa potency, product specific differences were noted between the products and the US generic enoxaparin showed a cumulatively stronger activity in most of the assays. To further test the pharmacodynamic profile of these products, individual groups of monkeys (n=4–8) were administered with each product at a 1 mg/kg SC and blood samples were collected for up to 28 hours. Clot based assays such as the APTT, Heptest, thrombin time, amidolytic anti-Xa and anti-IIa activities were carried out. In addition, tissue factor pathway inhibitor (TFPI) antigen, thrombin activatable fibrinolysis inhibitor (TAFI) activity and thrombin generation assays were also performed. Variable differences were noted in the clot based and amidolytic assays. Interestingly, the US generic product exhibited a lower release in the TFPI antigen whereas in the thrombin generation assays it produced a stronger inhibition of thrombin in terms of the AUC. TAFI activity profile also showed wide variations. These differences were more prevalent during the 1–4 hour time period. No differences were noted at >6 hours. The hysterisis PK/PD plots revealed marked differences between the two products. These results indicate that the products for the same generic suppliers may exhibit variations according to market places. Moreover, these observations underscore the need for a more stringent pharmacodynamic profile to demonstrate product equivalence. Disclosures:No relevant conflicts of interest to declare.

Recurrent Life-Threatening Deep Tissue Hematomas After Switching to Generic Enoxaparin: A Report and Perspective on the Approval Process for Biological Compounds

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.

The United States Food and Drugs Administration Approves a Generic Enoxaparin

The Food and Drug Administration (FDA) approved on July 23, 2010, the abbreviated new drug application (ANDA) by Sandoz Inc for a generic enoxaparin (Lovenox) as the FDA is satisfied with the active ingredient ''sameness'' and the interchangeability of Lovenox with this generic version. Regulatory authorities that consider low-molecular-weight heparins (LMWHs) as drugs approve generic LMWHs via an ANDA pathway, whereas EMEA views them as biological medicines and will therefore regulate copies of LMWHs via a biosimilar pathway because only similar copies can be manufactured. Furthermore, European Medicines Agency (EMEA) requires appropriately powered clinical trails to establish comparable efficacy and safety profiles for biosimilar and their branded LMWHs counterparts. The safety issues that have led to withdrawal of some generic LMWHs from some Asian and South American countries mandate the need for a broad consensus defining the minimum attributes copies of LMWHs required for efficacy and safety.

Comparison of Seven Generic Enoxaparins with Lovenox® on In Vitro Cross-Reactivity with Antibodies From Heparin Induced Thrombocytopenia.

AbstractAbstract 1105 Introduction:Heparin induced thrombocytopenia (HIT) is the major complication of heparin treatment but is less frequent in patients treated with low molecular weight heparins (LMWHs) than with unfractionated heparin (UFH). Cross immunological reactions of LMWHs with HIT antibodies from patients treated with UFH is a common finding. The immunological profile is among the criteria for similarity of a generic LMWHs. The cross reactivity of generic LMWHs with HIT antibodies has yet to be compared with the innovator product. Aim:To compare the profile of platelet aggregation induced by HIT antibodies in the presence of Lovenoxâ or seven generic enoxaparins. Methods:Platelet activation by HIT antibodies in the presence of UFH (Héparine Choay, France), branded enoxaparin (Lovenox®) and 7 generics (Novex®, Enoxa®, Dilutol®, Versa®, Cutenox®, Loparin®, Fibrinox®) was assessed by Multiple Electrode Aggregometry (MEA, Multiplate, Dynabyte, Germany) according to previously published assay1. Briefly, whole blood (340 μl) from 5 individual healthy donors was incubated with pooled platelet poor plasma (200 μl) from well characterised HIT positive patients and 40 μl of UFH or Lovenox® or generic enoxaparins yielding a final concentration of 1 anti-Xa IU/ml. Platelet aggregation was recorded over 15 min and the area under the curve (AUC, AU*min) was determined. Results:UFH and branded enoxaparin showed high cross reactivity with HIT antibodies in 4 out of 5 experiments. All of the 7 generic enoxaparins gave also a high positive cross-reactivity but the intensity of platelet aggregation varied. The magnitude of the response was classified as follows: Versa® > Enoxa® > Lovenox® > Novex® > Fibrinox® > Cutenox® > Loparin® > Dilutol®. In one experiment Lovenox® showed border-line cross-reactivity with HIT antibodies. Among generic enoxaparins Versa® showed the same extent of cross reactivity as that of Lovenox®. The other generic enoxaparins did not cross react with HIT antibodies. Conclusions:This is the first study that provides key data on the comparison of in vitro cross reactivity with HIT antibodies of generic enoxaparins versus Lovenox®. In the presence of a cross-reactivity of the originator enoxaparin with heparin-PF4-IgG immune complex, there is also a cross-reactivity of the 7 studied generic enoxaparins. The intensity of cross-reactivity is an additional criterion for comparison of generic LMWHs and the originator one. The differences on the intensity of cross reactivity follow the same pattern in the case of border line cross reactivity of the originator enoxaparin.

Inhibition of Thrombin Generation: An Additional Biological Criterion for the Evaluation of the Anticoagulant Mechanism of Action of Generic LMWHs

AbstractAbstract 3334 Background.All low molecular weight heparins (LMWHs) exert their antithrombotic effect primarily via the binding of pentasaccharide domain on antithrombin but vary in physicochemical properties, anti-Xa/anti-IIa ratios, and their effect on global coagulation tests such as the inhibition of thrombin generation (TG). Definition of criteria for biological similarity between generic LMWHs and the original product is a challenging issue. Aim of the study.We evaluated the capacity of Lovenox® and seven generic enoxaparins to inhibit TG in platelet poor and platelet rich plasma (PPP and PRP). Materials and Methods.Citrated PPP and PRP from 15 healthy volunteers was spiked with increasing concentrations (2-20 μg/ml) of Lovenox®, Novex®, Enoxa®, Dilutol®, Versa®, Cutenox®, Loparin®, Fibrinox®. Platelet count in PRP was adjusted to 200 /L. The anti-Xa and anti-IIa activities in PPP were measured on STAR analyser using chomogenic assays from Diagnositca Stago. Thrombin generation in fresh PPP and PRP was triggered with PPP-reagent® and 1/200 diluted Innovin® (from Siemens) respectively and assessed with Calibrated Automated Thrombogram® (Stago, France). Mean Rate Index (MRI) of the propagation phase of TG and endogenous thrombin potential (ETP) were analysed. The enoxaparin concentrations which reduced 50% of theTG parameters (IC50) were calculated. Results.All studied compounds showed the same anti-Xa activity/mg and anti-Xa/anti-IIa ratio as the comparator Lovenox®. The IC50 for MRI and ETP in PPP was not significantly different between Lovenox® and each one of the generic enoxaparins. In PRP the IC50 of Lovenox® for MRI and ETP was significantly lower compared to the generic enoxaparins. The IC5O of Fibrinox®, Dilutol®, Cutenox® and Versa® was 1.5- to 2-fold higher compared to that of Lovenox® (Table 1). Conclusion.Lovenox® and seven generic enoxaparins were the same in terms of anti-Xa activity/mg and anti-Xa/anti-IIa ratio. They exerted similar inhibitory effect on thrombin generation in PPP. In contrast, in the presence of platelets, the sameness and even the biological similarity of the studied compounds are not evident. The reasons for these diversities need to be elucidated. The results of the present study introduce the inhibition thrombin generation in platelet rich plasma as an additional biological criterion for the comparison of generic LMWHs to the innovator product. Disclosures:No relevant conflicts of interest to declare.

Priority Review from Denosumab for Bone Metastases, Orphan Drug Status from BiovaxID, Approval of Generic Enoxaparin

Priority Review from Denosumab for Bone Metastases, Orphan Drug Status from BiovaxID, Approval of Generic Enoxaparin

Bioequivalence of generic and branded subcutaneous enoxaparin: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy Chinese male subjects

Background: Enoxaparin is a low-molecular-weight heparin (LMWH) indicated for antithrombosis. A branded formulation of subcutaneously administered enoxaparin has been available in China since 2000, and a generic formulation is being developed. In a literature search of the key term enoxaparin (publication years not restricted), no published data were identified regarding the pharmacokinetic profile of generic enoxaparin in Chinese subjects. Objective: The aim of this study was to determine the bioequivalence of generic (test) and branded (reference) formulations of enoxaparin 60 mg (6000 IU anti-Xa) SC in healthy subjects for the purpose of meeting regulatory requirements for marketing the generic formulation in China. Methods: Healthy Chinese male volunteers were eligible for this single-dose, randomized-sequence, open-label, 2-period crossover study. Participants were randomly assigned to receive the test and reference formulations of enoxaparin 60 mg SC injection (fasting state) in randomized order, with the 2 study periods separated by a 1-week washout period. For the assessment of anti-Xa and anti-IIa activities (surrogates used to describe the pharmacokinetic properties and bioavailability of LMWH), heparin clotting assay, and activated partial thromboplastin time (aPTT), blood samples were obtained before (hour 0; baseline) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours after study drug administration. The 2 formulations were to be considered bioequivalent if the 90% CIs for the logarithm-transformed values of C max, T max, AUC 0−t, and AUC 0−∞ fell within the predetermined range of 80% to 125%. Tolerability was assessed by questioning subjects about symptoms of possible adverse events and using laboratory analysis (hematology, biochemistry, hepatic function tests, and urinalysis). Results: Twenty-two subjects participated in the study (mean [SD] age, 21.10 [1.02] years [range, 19–23 years]; weight, 64.07 [5.93] kg [range, 54–75 kg]; and height, 173 [5] cm [range, 163–187 cm]). For anti-Xa activity, the 90% CIs of C max, AUC 0−t, and AUC 0−∞ were 100.4% to 106.7%, 100.7% to 105.8%, and 100.7% to 106.1%, respectively. Corresponding values for anti-IIa activity were 85.0% to 102.4%, 80.4% to 94.8%, and 80.1% to 96.0%. For the hepa-rin clotting assay, the values were 97.4% to 102.4%, 98.2% to 102.4%, and 96.0% to 102.7%; and for aPTT, values were 98.2% to 104.3%, 97.4% to 101.6%, and 93.4% to 117.4%. No adverse events were reported during the study. Conclusions: Based on the 90% CIs of anti-Xa and anti-IIa activities, heparin clotting assay results, and aPTT in these healthy Chinese male subjects, the test and reference formulations of enoxaparin 60 mg SC met the regulatory requirements for bio-equivalence. Both formulations were well tolerated.

Biomarkers and Coagulation Tests for Assessing the Biosimilarity of a Generic Low‐Molecular‐Weight Heparin: Results of a Study in Healthy Subjects With Enoxaparin

Low-molecular-weight heparins (LMWHs) differ considerably in their influence on clotting tests and release of tissue factor pathway inhibitor (TFPI). Biosimilarity therefore becomes an issue when generic forms of LMWHs are developed. So far, no bioequivalence study with a generic LMWH has been reported. A generic enoxaparin (test) was compared with the originator (reference) in 20 volunteers after single-dose subcutaneous administration (40 mg enoxaparin sodium, 4000 IU/mL anti-factor Xa (anti-FXa; activity). Target variables were anti-FXa and anti-FIIa activity, activated partial thromboplastin time (aPTT), prothrombinase-induced clotting time (PiCT), and TFPI over 24 hours. The statistical evaluation of the anti-FXa activity profile demonstrated bioequivalence of test and reference with confidence intervals of area under the plasma concentration-time curve (AUC0-tlast) (93%-99%) and Amax (88%-95%). Confidence intervals of AUC(0-tlast) (89%-102%) and Amax (90%-103%) of anti-FIIa activity also fulfill bioequivalence criteria. The 90% confidence interval for the maximum concentration of TFPI ranged from 90% to 113%. The claim of similarity was also supported by aPTT and PiCT profiles. Bioequivalence with the originator enoxaparin could be demonstrated by ex vivo inhibition of FXa and FIIa activity, by coagulation tests (aPTT and PiCT), and by in vivo release of TFPI. Whether such data also prove biosimilarity of the generic enoxaparin needs to be determined.