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Contributions to this column are prepared by the Institute for Safe Medication Practices Canada (ISMP Canada), a key partner in the Canadian Medication Incident and Prevention System. From time to time, ISMP Canada invites others to share learning based on local initiatives. The article presented here is reprinted, with permission, from the ISMP Canada Safety Bulletin 2009;9(5):1–2.
ISMP Canada received a report of a medication incident in which Advagraf (an extended-release formulation of tacrolimus for oral administration) was dispensed to a patient instead of the intended Prograf (an immediate-release oral formulation of the same drug). Recent reports from the United Kingdom1,2 and Europe3,4 have documented mix-ups between Prograf and Advagraf and have outlined concerns about the outcomes of such incidents. According to these warnings, mix-ups between Prograf and Advagraf have led to serious harm, including cases of biopsy-confirmed acute rejection of transplanted organs and toxic effects due to overexposure. Although this incident occurred in a community pharmacy, it is an important alert for hospital pharmacists about the potential for serious patient harm if these drugs are mistakenly interchanged.
A patient who had undergone renal transplantation received a prescription refill from her community pharmacy for Prograf 1 mg to be taken every 12 hours. Advagraf 1 mg was dispensed with instructions for twice-daily dosing. Fortunately, the patient recognized that the capsules in the prescription bottle she had received had a different appearance from those in her previous prescription. The patient contacted her transplant program, and it was determined that Advagraf had been dispensed instead of the prescribed Prograf.
The following factors were identified as potential underlying causes of this mix-up:
Prograf was approved for use in Canada in December 1995.5 It is indicated for the prevention of organ rejection in patients who have received allogeneic liver, kidney, or heart transplant and for the treatment of refractory rejection in patients who have received allogeneic liver or kidney transplants, as well as for treating some cases of rheumatoid arthritis in adults.6 Advagraf was approved for use in Canada in October 20075 and was made available on the market in April 2008.7 It is indicated for the prevention of organ rejection in adult patients who have received allogeneic kidney transplant.8 Both Prograf and Advagraf contain the immunosuppressant tacrolimus; however, Prograf is an immediate-release formulation to be taken every 12 hours when used for the prevention of organ rejection, whereas Advagraf is an extended-release formulation that is to be taken every 24 hours.6,8 Tacrolimus has a narrow therapeutic index and highly variable pharmacokinetics; it requires individualized dosing based on the results of careful therapeutic monitoring. It is imperative that Prograf and Advagraf be prescribed, dispensed, and taken correctly to ensure that blood levels of tacrolimus are maintained within the therapeutic range.6,8
The following attributes may increase the potential for a mix-up between Prograf and Advagraf: the 2 formulations contain the same generic medication (tacrolimus); both medications are indicated for use after organ transplantation; both are available in a capsule format, for oral use, in the same dosage strengths (0.5 mg, 1 mg, and 5 mg); the product names are similar, both ending in “graf”; the two drugs are produced by the same manufacturer; and Prograf may be prescribed daily (for the treatment of rheumatoid arthritis), rather than twice daily, such that dosing frequency may not provide a cue as to which medication is intended.
ISMP Canada reviewed 33 medication incidents involving these drugs that have been reported internationally. In most of these incidents, the mix-up between Prograf and Advagraf occurred during prescribing and/or dispensing. The following common themes were identified from these error reports:
The following recommendations and considerations are provided:
ISMP Canada has informed Health Canada about the Canadian report received and the information highlighted in this article. Astellas Pharma Canada Inc, the manufacturer of both Prograf and Advagraf, is also aware of these issues and is supportive of ISMP Canada sharing this information. Astellas Pharma Canada Inc is working to implement various measures to reduce the potential for mix-ups between Prograf and Advagraf.
ISMP Canada gratefully acknowledges the expert review of this article by (in alphabetical order): Patti Cornish, RPh, BScPhm, Patient Safety Service, Sunnybrook Health Sciences Centre; Jennifer Harrison, BScPhm, MSc, Pharmacy Clinical Site Leader, University Health Network; Nicola Rosaasen, BSc, BSP, Pharmacist, Saskatchewan Transplant Program; Jeffrey Schiff, MD, FRCPC, Multi-Organ Transplant Program, Toronto General Hospital; John W Senders, PhD, Professor Emeritus, University of Toronto; Anita Wong, BScPharm, Rexall Outpatient Pharmacy, University of Alberta Hospital; and Ken Wou, BSc(Pharm), pharmacy consultant.
Medication incidents (including near misses) can be reported to ISMP Canada in 1 of 2 ways: