Skin necrosis induced by generic enoxaparin
Authors: Ayca Gucalp, Rekha Parameswaran, Mario Lacouture, Ghassan Abou‐Alfa, Gerald Soff
Journal: American Journal of Hematology (2013)

Heparin-induced skin necrosis is a rare complication of heparin or low molecular weight heparins (LMWH) 1. Cases generally are associated with antibodies to the heparin:platelet factor 4 complex and/or heparin-induced thrombocytopenia (HIT) 2. A recent review identified only 25 cases of skin necrosis associated with LMWH through May, 2009 3. In July 2010, the Food and Drug Administration (FDA) approved generic enoxaparin sodium 4. At our institution, we observed four cases of enoxaparin-induced skin necrosis in the initial 18-months since switching from the branded Lovenox® to generic enoxaparin (Sandoz). As we had not observed any cases in several years previously, this raised a concern of a greater risk of heparin-induced skin necrosis with the generic formulation. Case 1: A 67-year-old female with metastatic uterine carcinosarcoma was on therapeutic Lovenox® for over 3 weeks for a deep vein thrombosis (DVT). Within 24 hr of transitioning to generic enoxaparin, she developed necrotic lesions at the injection sites (Fig. 1A,B). The Heparin-Dependent Antibody (HDA) test (GTI® PF4 Enhanced®) was negative. Scarring persisted for over 6 months. Case 2: A 49-year-old male with metastatic colorectal adenocarcinoma tolerated a single unfractionated heparin infusion in an intra-hepatic artery infusion pump for localized chemotherapy delivery as well as brief exposure to generic enoxaparin prophylaxis during hospitalization. Ten days later, he was readmitted for infection and the first three doses of prophylactic generic enoxaparin resulted in injection site necrosis (Fig. 1C,D). HDA assay was strongly positive, (optical density, OD: 2.637), but he did not develop thrombocytopenia or thrombosis. Case 3: A 57-year-old female with metastatic colorectal adenocarcinoma underwent insertion of an intra-hepatic artery infusion pump. On post-operative day 1, the patient was placed on prophylactic generic enoxaparin sodium. On Day 13 of enoxaparin, the patient developed two local skin necrosis reactions. HDA assay was positive (OD: 3.217), as was the serotonin release assay. However, the patient neither developed thrombocytopenia nor thrombosis. Case 4: A 30-year-old woman, with steroid-controlled chronic immune thrombocytopenic purpura, was found to have a proximal DVT and was started on enoxaparin treatment. Beginning on Day 3, she developed inflamed injection site reactions, which progressed over the subsequent several days to necrosis. Her heparin dependent antibody assay was negative (OD: 0.199) and she did not develop thrombocytopenia nor new thrombosis. Hyperpigmented skin changes persisted beyond 6 months. Generic enoxaparin has quickly achieved widespread use for thrombosis prophylaxis and treatment due to its reduced cost. Our cluster of cases raises a question of possible increased risk of skin necrosis with generic enoxaparin compared with brand named Lovenox®. To the best of our knowledge, these are the first reported cases attributed to generic enoxaparin. It is noteworthy that in just one institution we observed four cases in the first 18 months since introduction of generic enoxaparin. Several characteristics of our four cases are distinct from previously published cases. Most cases of heparin-induced skin necrosis have been associated with HDA, and/or thrombocytopenia 3, 5. In contrast, none of our patients exhibited thrombocytopenia, new thrombosis, or clinical HIT, and only 2 of our 4 cases exhibited a positive HDA assay. Further, in two cases the skin necrosis developed outside the usual time-frame of HIT of 5–15 days of exposure (Cases no. 1 and 4) 5. These novel features suggest a novel mechanism of the pathology. In 2010, the FDA approved generic enoxaparin sodium injection under the FDA's Abbreviated New Drug Application pathway (4). Approval was based on in vitro analysis and immunogenicity studies in healthy volunteers with only limited human clinical trial experience. An FDA bulletin claimed, “With the FDA approach, there is no scientific need to perform additional clinical studies to demonstrate equivalence of clinical effectiveness and safety of generic enoxaparin to Lovenox” 4. A full discussion of the appropriateness of the FDA approval process in the case of generic enoxaparin is beyond the scope of this brief report. However, our four cases of skin necrosis raise the possibility that an increased risk of this relatively uncommon, but potentially severe adverse event, may exist and was not identified in the abbreviated approval process. Ayca Gucalp Rekha Parameswaran Mario Lacouture Ghassan Abou-Alfa Gerald A. Soff Memorial Sloan-Kettering Cancer Center, Department of Medicine