An Evaluation of Off-Label Use of Recombinant Activated Human Factor VII (NovoSeven)

INTRODUCTION Recombinant activated coagulation factor VII (rFVIIa) is a hemostatic agent developed by Novo Nordisk Pharmaceuticals, Inc., under the trademark NovoSeven. It is a recombinant DNA preparation of a naturally occurring protease, activated blood coagulation factor VII. It is nearly identical to plasmaderived activated factor VII in its pharmacokinetics, structure, and function. The FDA approved this drug in March 1999 for the treatment of bleeding episodes in patients with hemophilia A or B who have inhibitors to factor VIII or factor IX. Several characteristics of rFVIIa, such as lack of systemic activation, non-reactivity with other circulating inhibitors, and low infusion volume, make it potentially useful for treating bleeding disorders other than hemophilia. As a result of the increasing off-label use of rFVIIa, concerns have arisen about its efficacy, safety, and cost to the health care system. rFVIIa is supplied as single-use vials in dosage strengths of 1.2, 2.4, and 4.8 mg per vial. The labeled dosage is an infusion of 90 mcg/kg of body weight every two to three hours. The average wholesale price of the drug is $1.48 per mcg. Thus, the typical cost of treatment of an adult man weighing 80 kg would be more than $10,000 per dose. Shander et al., in their review of the literature, reported that it is not uncommon for hospitals to have rFVIIa expenditures exceeding $500,000 a year, most of it related to off-label use. In a study conducted by Blatt et al., the off-label use of rFVIIa resulted in hospital costs ranging from $10,000 to $200,000 per patient. MacLaren et al., in their study of 315 patients in 21 hospitals, documented that the median cumulative dose was 90 mcg/kg, given one time. Since 1999, an increasing number of reports and published studies have described the efficacy of rFVIIa for off-label uses. Its off-label use as a hemostatic agent for massive bleeding in various conditions is rapidly expanding. These conditions include coagulopathies in newborns, severe liver disease, high-risk surgeries, blood loss from trauma, bone marrow transplantation, thrombocytopenias and platelet function disorders, critical reversal of oral anticoagulation, congenital deficiencies of factor VII and factor XI, von Willebrand disease, and refractory bleeding after making a transition from an ABSTRACT Background. Recombinant activated factor VII (rFVIIa), which has been approved by the Food and Drug Administration for the treatment of bleeding in patients with hemophilia, is increasingly being used to control or prevent bleeding in a variety of clinical situations. However, its widespread use is raising concerns in terms of its efficacy, safety, and cost. The objective of our study was to examine the “on-label” and “off-label” uses of rFVIIa in academic medical centers in the U.S. Methods. Our descriptive retrospective administrative database study included all patients with a hospital-based charge for rFVIIa during their inpatient stay. Patients with hemophilia were categorized as receiving rFVIIa for on-label use; all other uses were considered off-label. We analyzed the variables of age, sex, ethnicity, principal payer, admission source and status, physician specialty, severity-of-illness score, principal and secondary diagnoses and procedures, and Diagnosis-Related Groups. We evaluated overall length of stay (LOS), LOS in the intensive care unit (ICU), total hospital costs and charges, and patient discharge status. Results. The analysis included 2,660 cases from 40 hospitals. Overall, 89% of rFVIIa usage was classified as off-label. Patients receiving rFVIIa for off-label use had a higher degree of severity of illness, longer overall LOS, longer ICU LOS, and a higher mortality rate. Despite the obvious differences between the two patient populations, hospital costs and charges were similar for both off-label and on-label uses. Conclusion. Most rFVIIa use in these academic medical centers is off-label, and its utilization is increasing. General surgeons, internists, and cardiothoracic surgeons are the specialists who prescribe this medication most frequently. Treated patients tend to be of high acuity (with complicated illnesses) and represent those with a broad array of disease states. This study describes a rapid method of evaluating the clinical use of high-impact pharmaceuticals such as rFVIIa, and we hope that it will be helpful in targeting future efforts in developing appropriate guidelines.