Prograf (tacrolimus, FK506) is a potent immunosuppressant indicated for the prophylaxis of organ rejection in allogeneic liver transplant patients. We report here a summary of 12 cases of acute overdoses received by Fujisawa USA, Inc. since the drug became commercially available in April 1994. In 11 cases, overdosage occurred with a single dose and was not perpetuated with further doses. In the twelfth case, an accidental overdose was taken on three occasions over 2 consecutive days. Four reports were of suicide gestures/attempts, and eight were the result of medication errors. Detailed information, including outcome, is unavailable for one patient. Of the remaining 10 patients (age range, 1-44 years), overdosage of up to 30 times the intended dose occurred. All intentional overdoses occurred with the oral capsule formulation. Unintentional overdose cases were reported with both the oral and the intravenous tacrolimus formulations.
Three patients were asymptomatic after accidental overdose, whereas seven individuals exhibited mild, transient signs and symptoms; these included mild elevations of renal function markers (blood urea nitrogen and creatinine), nausea, mild hand tremors, and elevations of liver enzymes. One additional patient developed renal failure, histoplasmosis, and sepsis 2 days after admission for the overdose; because this patient was receiving maintenance tacrolimus therapy before the acute overdosage, it is unknown to what extent the tacrolimus overdose contributed to these events. In each of these eight symptomatic cases, all symptoms and toxicities resolved after either temporary discontinuation of tacrolimus (in the presence of elevated tacrolimus whole blood levels) and/or resumption of the intended dosing schedule. Whole blood tacrolimus concentration was 19 ng/ml in the patient who received an overdose on three consecutive dosing occasions, and concentrations ranged from 51.6 to 197 ng/ml in the remaining cases. All signs and symptoms resolved within a few days with no sequelae.
The following procedures have been used in the management of these patients: (1) gastric lavage, (2) orally activated charcoal(1), (3) phenytoin administration (for seizure prophylaxis and the enhancement of tacrolimus metabolism through stimulation of cytochrome P450), and (4) close clinical observation for signs/symptoms of tacrolimus toxicities as identified in the package insert.
Although the measures described above have been used successfully in managing acute overdoses, to date there is insufficient experience to recommend specific treatment measures. The above treatments are consistent with the known pharmacokinetics and safety profile of this drug. We do not believe that hemodialysis would be clinically useful because of the lipophilicity and relatively large molecular weight of tacrolimus (822 daltons), and its extensive tissue and protein binding(2). No information is available concerning charcoal hemoperfusion.
Despite occasional serious adverse events associated with the chronic use of tacrolimus after organ transplantation, acute exposures in both healthy individuals and in transplant patients have not resulted in any long-lasting adverse effects or fatalities thus far. Mortalities have been reported in adult and immature rats orally dosed at 52 times and 16 times, respectively, the recommended human oral dose (3).
Charles F. Curran1
Paul C. Blahunka
Ira D. Lawrence
Fujisawa USA, Inc.; Deerfield, Illinois 60015
1. Mrvos R, Hodgman M, Dean B, Krenzelok E. FK506 overdose: a report of four cases. Clin Toxicol 1995; 33: 487.
2. Nagase K, Iwasaki K, Nozaki K, Noda K. Distribution and protein binding of FK506, a potent immunosuppressive macrolide lactone, in human blood and its uptake by erythrocytes. J Pharm Pharmacol 1994; 46: 113.
3. Fujisawa USA, Inc. Prograf© (tacrolimus) prescribing information. Deerfield, IL: Fujisawa USA, Inc., 1996.