We need generic low-molecular weight heparins

Issue: January 10, 2009

ByStephen B. Shohet, MD

A year ago, I was asked by a small pharmaceutical company in Southern California to compare the biochemical characteristics of their generic low-molecular weight heparin enoxaparin to Lovenox, the FDA-approved proprietary product manufactured by Sanofi-Aventis. For that review, I considered a large amount of data provided to the FDA as part of a long-standing application for approval of the generic product. Among other things, I found that the polysaccharide chain lengths, the anion distributions, the sulfate ion concentrations, the number of 1,6 anhydro rings, and the sugar epimer distributions were all identical in the proprietary and generic preparations.

I was subsequently asked to present my findings to an ad hoc committee at the FDA on Nov. 19, 2007. The committee was chaired by Janet Woodcock, MD, the director of the Center for Drug Evaluation and Research. I presented a detailed summary of my findings and additionally noted that the trace amount of protein in even the unhydrolyzed starting material used for both products was unlikely to cause any immune reactions. I concluded that in clinical use the generic enoxaparin “… will behave the same as Lovenox, both functionally and immunologically.”

Stephen B. Shohet, MD
Stephen B. Shohet

Heparin is given as an anticoagulant to nearly 11 million patients each year in the United States. Around two-thirds are treated with UFH, while the rest are treated with proprietary LMWH. Only a fraction of patients receive the drug intensively for vascular surgery, postsurgical prophylaxis or established thrombosis. However, a surprising number of such patients, perhaps 1% to 3%, developed the “prothrombic disorder characterized by activation of the coagulation system” termed heparin-induced thrombocytopenia (HIT). About one-fifth of those patients will progress to the more serious thrombotic condition, heparin-induced thrombocytopenia with thrombosis (HITT). Even with improved recognition and replacement anticoagulants, about 15% of patients who developed HITT die from pulmonary emboli or other serious thromboembolic events. An additional 20% suffer from serious permanent complications, such as extremity ischemia with amputations, strokes and extensive venous disease with post-phlebitic consequences.

Fortunately, such patients treated with LMWH are much less likely to develop HIT than similar patients treated with UFH. Even if the progression to HITT is the same — and it may be less — there is at least a 15-fold reduction in death and permanent disability for patients treated with LMWH. Considering these differences, for intensively treated patients the low molecular weight product is clearly medically preferable in terms of avoiding the dreaded complications of HITT. Because it is given subcutaneously and usually requires no laboratory monitoring, it is also preferable in terms of patient and physician convenience. Some patients can even undertake their heparin therapy at home.

Unfortunately, the proprietary LMWH was, until recently, more than 20 times as expensive as UFH. Several cost-effectiveness studies have shown that overall hospitalization costs are not influenced by this difference in drugs costs. One recent large study of patients with DVT even showed a $1,000 savings in total costs with LMWH. However, despite these analyses, the major drug cost difference carried in hospital formularies has inhibited more universal use of LMWH.

Generic drugs are usually 40% to 60% less expensive than their proprietary equivalents. If generic LMWH were available, it is reasonable to anticipate that the use of UFH would be reduced by at least one-third in patients requiring anticoagulation. (Some patients would still benefit with UFH because of its useful short half-life, safety in patients with renal failure and rapid reversibility with protamine.)

Because of profound differences in the incidence of HITT in different clinical populations and because of a significant likelihood of over-diagnosis with some immunologic assays, it is difficult to draw conclusions on the utility of such a shift in the entire population of the United States. However, a mixed population of 1 million people has been monitored in Hamilton, Ontario, where patient detection is both sensitive and accurate because of referral of all patients to a single center using the preferred serotonin-release assay for diagnosis. In that population, approximately 30 patients with HITT are diagnosed each year. From that number it is possible to construct a theoretical picture of the effect of a shift in the usage of heparin from a current usage ratio (UFH:LMWH) of nearly 3:2 to a new usage ratio of 2:3. This scenario is presented in the table.

$Theoretical Effect of a One-Third Reduction in the Use of Unfractionated Heparin$

As can be seen, the reduction in direct medical costs in terms of death and disability is impressive. The reduction in indirect societal costs from missing and maimed patients would also be substantial.

The FDA has been considering at least three different candidate LMWH preparations for between three and five and a half years. Further, one year ago, for one of these generic preparations, the director of the Office of Generic Drugs at the FDA confirmed that “no further documentation (of) active ingredient sameness (compared to Levenox) is necessary.” Finally, exhaustive testing both in vitro and in animals has shown no differences in immunogenicity or toxicity between that generic and Lovenox.

It is time for the FDA to approve generic LMWH so that more of our patients can benefit from this superior mode of heparinization.

Stephen B. Shohet, MD, is Emeritus Professor of Medicine and Laboratory Medicine at the University of California, San Francisco.

Amphastar Pharmaceuticals requested the comparison of products. This request was to provide background for Dr. Shohet’s testimony before the FDA. He has not appeared in any other capacity on this company’s behalf.

For more information:
Warkentin TE, Greinacher A. Heparin-induced Thrombocytopenia, 4th Edition (in Preface to 1st Ed.), Informa (pub), 2007.
Daneschvar HL, Daw H. Heparin-induced thrombocytopenia, (an overview). Intl J Clin Prac. 2007;61:130-137.
Martel N, et al. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta analysis. Blood. 2005;105:2710-2715.
McGarry LJ, et al. Cost effectiveness of thromboprophylaxis with a low-molecular-weight heparin versus unfractionated heparin in acutely ill medical inpatients. Am J Managed Care. 2004;10:632-642.
Weinberg RM, et al. Cost implications of using unfractionated heparin or enoxaparin in medical patients at risk for venous thrombotic events. Pharm & Therapeutics. 2006;31:322-333.
Warkentin TE, et al. Impact of the patient population on the risk for heparin induced thrombocytopenia. Blood. 2000;96:1703-1708.
Lo GK, et al. What is the potential for over diagnosis of heparin-induced thrombocytopenia? Am J Hematol. 2007;82:1037-1043.
Warkentin TE. Personal communication.