Potentially serious medication errors with a new once-daily preparation of tacrolimus (Advagraf™).

Abstract

Sir, Tacrolimus is a widely used immunosuppressant drug in solid-organ transplantation. A new once-daily formulation (AdvagrafTM, Astellas, Tokyo) has been licensed in Europe in 2007 and shown to be safe and efficacious [1,2]. It is conceivable that the new formulation offers an advantage regarding compliance when compared to twice-daily Tacrolimus (PrografTM, Astellas) although this remains unproven. A 31-year-old renal transplant recipient with stable transplant function [glomerular filtration rate (GFR) 27 ml/min] was maintained on PrografTM 2.5 mg BD and prednisolone. While participating in a teaching event in November 2008, she produced a box of once-daily Tacrolimus (AdvagrafTM) and stated that she had taken this ‘new’ drug twice daily for 2 months. A mild rise in Tacrolimus blood levels was noted although her GFR had remained stable. We prescribed PrografTM and investigated the incident. It transpired that she ordered repeat prescriptions through a web-based system (EMISaccessTM, Egton Ltd, Leeds, UK). When updating her medication, the GP had erroneously chosen AdvagrafTM M/R (modified release) from the two options for Tacrolimus that the software provided but maintained treatment twice daily. AdvagrafTM had then been dispensed. However, the patient had not read the package insert and taken AdvagrafTM twice daily, as suggested by her medication plan, thus maintaining her previous total Tacrolimus dose. In December 2008, we double-checked her medication again. It turned out that she now took Prograf 2 mg BD and Advagraf 0.5 mg BD. Again, we rectified the error while GFR and Tacrolimus levels remained stable. We [3] and others [4] have previously voiced concern regarding two different formulations of Tacrolimus being available concurrently. This incident underpins our concern. No untoward consequences have occurred, chiefly because the patient took AdvagrafTM twice daily. Had she taken the drug according to the package insert, and halved her daily Tacrolimus dose, she may have sustained rejection and graft loss. Conversely, if transplant patients erroneously take AdvagrafTM twice daily, this may cause over-immunosuppression and infection with a potentially fatal outcome. Various healthcare providers are involved in prescribing the immunosuppression in transplant recipients. All of them should be very aware of this potentially life-threatening issue. We appreciate that Astellas takes this matter very seriously and we understand that the company plans additional warning labels on the package. Prescribing software should feature similar warnings and should not allow treatment with AdvagrafTM twice daily. Others, such as the health authorities in Wales, have decided against AdvagrafTM to avoid errors and because they feel that the drug does not convey any particular advantage over PrografTM [5]. We have alerted general practitioners and begun to scrutinize patients on Tacrolimus. We consider approaching all our transplant patients. Finally, we now provide an information leaflet to all patients whom we intentionally convert to AdvagrafTM. Conflict of interest statement. A.W. has given talks for Amgen, Pfizer and Sankyo and received honoraria. He has given one talk for the cardiovascular division of Novartis (a competitor of Astellas in transplantation) in 2007 and received honorarium. He has also participated in clinical studies in transplant patients with Novartis and Wyeth (another competitor of Astellas in transplantation). The other authors declare no conflict of interest.