E DITORIALS When Is Off-Label Drug Use in the Patient’s Best Interest? PHILIP J. ROSENFELD AND KENNETH W. GOODMAN I N THIS ISSUE OF THE JOURNAL, THEODOSSIADIS AND associates report on the first 3 patients receiving intra- vitreal infliximab (Remicade; Centocor Inc, Malvern, Pennsylvania, USA) for the treatment of neovascular age-related macular degeneration (AMD). 1 This report may represent a breakthrough therapy that will revolution- ize our management of patients undergoing anti–vascular endothelial growth factor therapy. This report also may spark debate as to whether these clinicians crossed the line between clinical care and unapproved research. In this prospective case series, the justification for using intravitreal infliximab was the apparent lack of efficacy with ranibizumab (Lucentis; Genentech Inc, South San Francisco, California, USA). Ranibizumab is the only approved treatment for neovascular AMD that has been shown to improve mean visual acuity (VA) in phase III clinical trials when given as monthly intravitreal injec- tions over 2 years. 2,3 However, in real-world clinical practice, patients rarely receive continuous monthly ther- apy. Patients usually receive 3 to 4 monthly doses followed by less frequent retreatments, depending on the patient’s response to therapy. Less frequent dosing is mentioned in the Food and Drug Administration (FDA)-approved pack- age insert for ranibizumab with the caveat that dosing less frequently may result in diminished VA when compared with monthly dosing. 4 The authors recommended intravitreal infliximab after a short course of ranibizumab therapy. Infliximab, a chimeric immunoglobulin G1 monoclonal antibody, binds specif- ically to human tumor necrosis factor  (TNF). In the United States, infliximab is FDA approved for several autoimmune diseases, including rheumatoid arthritis, Crohn disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis. 5 In the treatment of these immunologic diseases, infliximab is infused intrave- nously at loading doses ranging from 3 to 5 mg/kg given at baseline and then again at 2 and 6 weeks after the initial infusion. Maintenance therapy at doses up to 10 mg/kg then is given at intervals ranging from 4 to 8 weeks, depending on disease severity and the patient’s response to therapy. The first clinical evidence that systemic inflix- imab could improve the natural history of neovascular AMD was reported first by the same group. 6 Theodossiadis and associates offered off-label infliximab to their patients not as a systemic treatment, but as an intravitreal injection. This intravitreal infliximab was prepared in an off-label manner as well. Rather than reconstituting the 100-mg vial of lyophilized infliximab with the usual 10 ml sterile water, the authors used 5 or 2.5 ml sterile water to create more concentrated preparations of infliximab at 20 and 40 mg/ml, respectively (2 and 4). These higher concentrations permitted the authors to inject an intravitreal volume of 0.050 ml and to achieve doses of 1 and 2 mg. Theodossiadis and associates did not select this dose by accident. To their credit, they per- formed animal studies in rabbits and investigated a range of intravitreal doses. 7 Using electrophysiologic testing and histopathologic analysis, they concluded that a 2-mg dose may be safe in the human eye. When higher doses were injected in the rabbit eye, they identified drug-related toxicities. In their study, the dose-limiting toxicities were characterized by electrophysiologic dysfunction and his- topathologic abnormalities in the retina. Two aspects of off-label infliximab use not discussed by Theodossiadis and associates are the cost of the therapy and the stability of the drug. It is unlikely that any insurer, government or private, would knowingly cover the cost for such off-label drug use before the presentation of any evidence showing clinical efficacy. With a 100-mg vial of infliximab costing $604.00 in the United States ($6.04/ mg), the cost per patient would depend on the number of patients treated on any given day, because the package insert recommends that the infliximab solution be used within 3 hours of reconstitution. The authors do not address whether the reconstituted drug was stored and do not state the cost of therapy per patient. Even if 1 vial was used per patient, the cost for the entire vial ($604.00) is still less than a single-dose of ranibizumab ($1,950.00). Although ranibizumab may be the best FDA-approved treatment option currently available, its high cost probably influences treatment decisions; for example, although off- label intravitreal bevacizumab (Avastin; Genentech Inc) may have been used initially as salvage therapy in patients with neovascular AMD before the approval of ranibi- See accompanying Article on page 825. Accepted for publication Jan 26, 2009. From the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine (P.J.R.); and the Department of Medicine and Director of the Bioethics Program, Depart- ment of Medicine, University of Miami Miller School of Medicine (K.W.G.), Miami, Florida. Inquiries to Philip J. Rosenfeld, Bascom Palmer Eye Institute, Univer- sity of Miami Miller School of Medicine, 900 NW 17th Street, Miami, FL 33136; e-mail: prosenfeld@med.miami.edu © 2009 BY ELSEVIER INC.ALL RIGHTS RESERVED. 0002-9394/09/$36.00 761 doi:10.1016/j.ajo.2009.01.011