Full text of DOI:10.1592/phco.22.12.1063.33604

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C A S E R EP RTS
Severe Prolonged Tacrolimus Overdose with Minimal
Consequences
Laura L. Hardwick, Pharm.D., and Thomas D. Batiuk, M.D., Ph.D.
A 59-year-old man inadvertently received a 10-fold increase in his twice-daily
oral dose of tacrolimus 1 mg that resulted in trough blood levels above 90
ng/ml for over a week. The patient had end-stage renal disease secondary to
diabetes mellitus and had received a kidney transplant from his daughter 3
months earlier. Despite the numerous adverse effects commonly reported
with tacrolimus, such as mild nephrotoxicity, nausea, tremors, and elevated
liver enzyme levels, our patient’s acute but prolonged overdose resulted in
minimal signs and symptoms of toxicity. Nevertheless, education regarding
the importance of accurate dosing, close monitoring, potential drug
interactions, and the various capsule colors should be provided to all patients
who receive tacrolimus, as well as their physicians, nurses, and pharmacists,
in order to prevent as many errors as possible.
(Pharmacotherapy 2002;22(8):1063–1066)
Tacrolimus (FK 506, Prograf; Fujisawa
Healthcare, Inc., Deerfield, IL) is an immuno-
suppressant agent commonly administered to
prevent acute allograft rejection after solid organ
transplantation. Long-term administration of
tacrolimus has been associated with numerous
adverse effects, such as nephrotoxicity, neuro-
toxicity, electrolyte abnormalities, and glucose
intolerance.1, 2 Case reports of acute overdoses of
tacrolimus have not described the consequences
of significantly elevated levels sustained for an
extended period.3-8 Our patient had supra-
therapeutic tacrolimus levels for over 9 days.
hypertension received a living renal transplant
from his daughter. Aside from tremors and mild
confusion that were present before transplantation
and continued subsequently, the patient had an
uneventful recovery and was discharged 5 days
after his operation; his serum creatinine level was
0.9 mg/dl. His immunosuppressant regimen at
discharge consisted of oral prednisone 30 mg/day,
oral tacrolimus 1 mg twice/day, and oral
mycophenolate mofetil 1000 mg twice/day. His
trough tacrolimus level at discharge was 12.6
ng/ml (normal 5–15 ng/ml).
Three months after transplantation, the patient
was admitted to the hospital with symptoms of
an upper respiratory infection, an elevated blood
glucose level, changes in mental status, a 4-day
history of combativeness and confusion, and a 2-
day history of tremors. His tacrolimus level was
118.5 ng/ml. Because of a prescribing error, his
twice-daily dose inadvertently had been increased
from 0.5 to 5 mg 8 days before his hospital
admission. Neither the patient nor his wife had
questioned the different-color capsule that was
dispensed. His trough tacrolimus level 4 days
before his admission was 91.6 ng/ml. A mild
elevation in his aspartate aminotransferase level
(from 24 to 57 IU/L) and white blood cell count
Case Report
A 59-year-old, 79-kg man with end-stage renal
disease secondary to diabetes mellitus and
From the Department of Pharmacy, Indiana University
Hospital, Clarian Health Partners (Dr. Hardwick), the
Indiana University School of Medicine (Dr. Batiuk), and the
Department of Medicine, Roudebush VA Medical Center
(Dr. Batiuk), Indianapolis, Indiana.
Supported by a clinician scientist award from the
National Kidney Foundation and a merit review award from
the Veterans Administration.
Address reprint requests to Laura L. Hardwick, Pharm.D.,
BCPS, 550 North University Boulevard, UH 1451,
Indianapolis, IN 46202; e-mail: Lhardwic@clarian.org.

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PHARMACOTHERAPY Volume 22, Number 8, 2002
Table 1. Our Patient’s Laboratory Test Results
On Hospital
Admission
Normal
Range
Laboratory Test
Day 2
Days 3–4
Sodium (mEq/L)
Potassium (mEq/L)
Chloride (mEq/L)
Bicarbonate (mEq/L)
Blood urea nitrogen (mg/dl)
Creatinine (mg/dl)
Glucose (mg/dl)
Calcium (mg/dl)
140
4.3
102
18
143
4.4
112
19
—
—
—
—
—
—
—
9.1
135–145
3.5–5.5
95–105
22–27
21
13
5–20
1.1
532
10.0
3.4
—
0.8
188
9.4
< 1.0
—
0.8–1.4
65–200
8.4–10.6
2.5–4.9
1.6–2.9
4–7
Phosphorus (mg/dl)
Magnesium (mg/dl)
Uric acid (mg/dl)
2.7
0.7
3.4
—
—
Creatine kinase (U/L)
Cholesterol (mg/dl)
Albumin (g/dl)
—
—
4.2
—
—
17.7
50.4
200
1.1
27.2
118.5
—
—
3.5
—
—
18.8
48.2
218
—
—
80.7
61
152
—
66
29
—
—
—
—
50–180
120–200
3.5–5.0
25–125
25–45
4.5–11.5
14–18
150–450
0.9–1.1
24.7–33.4
5–15
Alkaline phosphatase (U/L)
Aspartate aminotransferase (U/L)
White blood cell count (x 103/mm3)
Hematocrit (%)
Platelets (x 103/mm3)
International normalized ratio
Partial thromboplastin time (sec)
Tacrolimus level (ng/ml)
—
54.6 (day 3)
25.0 (day 4)
(from 12.0 to 16.1 x 103/mm3) were the only
other biochemical abnormalities at that time.
His drug regimen on admission consisted of
prednisone, tacrolimus, mycophenolate mofetil,
doxazosin, atorvastatin, nifedipine, nefazodone,
sulfamethoxazole-trimethoprim, ranitidine, and
insulin. Atorvastatin was the only drug added
since his discharge after transplantation. Because
of the well-known drug interaction with
tacrolimus, the nefazodone dosage had not been
changed since transplantation. Except for
leukocytosis, hyperglycemia, and ketonemia, the
patient’s venous blood counts and laboratory
values on admission were essentially normal
(Table 1), as were his arterial blood gases (partial
pressure of oxygen 81 mm Hg, partial pressure of
carbon dioxide 35 mm Hg, pH 7.35). His
average serum creatinine level before the
tacrolimus overdose had been 0.9 mg/dl (range
0.7–1.0 mg/dl) since transplantation. Urinalysis
was remarkable only for a glucose level greater
than 1000 mg/dl and the presence of ketones.
Because of the patient’s worsened confusion, a
lumbar puncture was performed and empiric
antimicrobial therapy was started. Results of
cerebral spinal fluid analysis revealed elevated
glucose (151 mg/dl) and protein (108 mg/dl).
When culture results were obtained, all
antimicrobials were discontinued.
Throughout the patient’s course of therapy, his
serum creatinine level remained stable (Figure
1). His tacrolimus level was 9.8 ng/ml 6 days
after admission, and tacrolimus therapy was
restarted at 0.5 mg. Three days after therapy was
restarted, serial tacrolimus levels were obtained
to determine whether the patient’s absorption or
rate of elimination exhibited characteristics that
would better help us manage his tacrolimus
therapy (Figure 2). After 5 days, therapy was
Figure 1. Tacrolimus (ng/ml) and serum creatinine (mg/dl)
levels before and after the patient’s hospital admission for
tacrolimus overdose.

TACROLIMUS OVERDOSE WITH MINIMAL CONSEQUENCES Hardwick and Batiuk
1065
discontinued, and the patient was given
prednisone and mycophenolate mofetil as
immunosuppressive therapy to minimize the
risks of neurotoxicity associated with either
tacrolimus or cyclosporine. His confusion slowly
improved throughout his hospital stay but did
not resolve.
patients remained asymptomatic or exhibited
only mild, transient signs and symptoms. Main
manifestations of toxicity were mild
nephrotoxicity, nausea, tremors, and elevated
liver enzyme levels.3, 5, 8 Some patients were
treated with anticonvulsant therapy to induce
metabolism of tacrolimus.4, 7, 8 A metabolism-
inducing agent was not administered in this
situation due to the presence of relatively mild
toxicity and the possibility of confounding the
ability to restart and manage tacrolimus levels.
Our patient’s case was unusual in that his
tacrolimus levels remained at supratherapeutic
levels for at least 9 days, with trough levels above
90 ng/ml for at least 4 days.
Manifestations of tacrolimus toxicity in our
patient were fairly mild. Potassium levels were
higher than his previous posttransplantation
levels both on admission and during the period
of supratherapeutic tacrolimus levels; however,
none of the potassium levels were outside the
normal range. Phosphorus and magnesium
levels were extremely low during the first few
days after hospital admission. Blood pressure
was variable but not constantly elevated. Hepatic
dysfunction was mild, demonstrated by a
transient increase in aspartate aminotransferase.
The patient’s mental status was relatively worse
according to his wife, but examination revealed
no new or focal neurologic deficits. Onset of the
signs of tacrolimus toxicity may have been
masked due to the patient’s tremors and mild
confusion, which were present even before
transplantation.
Although these abnormalities have been
reported with tacrolimus, each one may reflect
complications of our patient’s poor glucose
control. Indeed, the main consequence of
tacrolimus therapy and overdose appears to have
been impaired diabetes therapy. Our patient’s
condition had been stable and well controlled by
administration of oral hypoglycemic agents
before transplantation, but he required insulin
afterward. His fasting blood glucose level,
measured in the hospital 1–2 times/week after
transplantation, was 65–326 mg/dl; most values
were above 150 mg/dl during the 2 months
before his hospital admission for tacrolimus
overdose. Home monitoring, performed several
times/day with a portable dextrose-monitoring
device, indicated that his blood glucose level was
usually 100–200 mg/dl, with infrequent
escalations above 500 mg/dl. His blood glucose
control worsened during the period of tacrolimus
overdose, including the initial blood glucose level
On hospital day 12, the patient’s urine output
decreased; a bladder scan revealed a dilated
bladder with 700 dl residual urine. A urology
consultant suggested restarting therapy with
doxazosin (which had been held since
admission) and scheduled intermittent urinary
catheterizations due to benign prostatic
hypertrophy with mild obstruction. Oral
doxazosin 2 mg at bedtime given before
admission was restarted at half the dose. The
patient was discharged 2 days later to a
rehabilitation facility. His drugs at discharge
were prednisone, mycophenolate mofetil,
sulfamethoxazole-trimethoprim, clotrimazole,
atorvastatin, ranitidine, lisinopril, doxazosin,
nefazodone, magnesium lactate, and insulin. He
was readmitted 2 weeks later with urosepsis that
was treated successfully with antibiotics. He
underwent a transurethral resection of the
prostate 1 month later, after which his mental
status dramatically improved to a level that
exceeded his pretransplant condition.
Discussion
Tacrolimus is a potent immunosuppressive
agent associated with many adverse reactions,
some of which are dose dependent.1, 2 In several
case reports of acute tacrolimus overdose,3–8
Figure 2. Serum tacrolimus levels over time immediately
before and for several hours after he received a 0.5-mg dose
to measure tacrolimus absorption.

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PHARMACOTHERAPY Volume 22, Number 8, 2002
of 532 mg/dl at his hospital admission. The
patient was managing his diabetes through
dietary modification alone since his tacrolimus
therapy was discontinued.
need for routine measurement of drug levels even
in patients whose conditions are stable. Careful
monitoring of tacrolimus levels is extremely
important given the drug’s narrow therapeutic
window, the risks of chronic toxicity, and the
multitude of drug interactions that may occur
anytime after transplantation. Management of
our patient’s acute overdose consisted solely of
monitoring for signs of toxicity and providing
supportive care. Education concerning the
importance of accurate dosing, close monitoring,
potential drug interactions, and the various
capsule colors should be provided to all patients
who receive the drug, as well as their physicians,
nurses, and pharmacists, in order to prevent as
many errors as possible.
The role of the patient’s urologic problems is
difficult to discern. Worsening confusion was
the chief clinical finding at the time of tacrolimus
overdose, but his confused state lasted for
approximately 1 month after tacrolimus levels
were undetectable and improved significantly
only after resolution of his urologic problems.
Whether a direct correlation, or any correlation,
exists between the patient’s urologic problems
and his confusion is unclear. Some confusion
may have been uremic in origin and may not
have resolved until several months after
transplantation. Another, not mutually
exclusive, possibility is that he experienced
continuing low-grade urinary tract infection that
augmented his pretransplantation confusion, and
that this infection resolved with resolution of his
benign prostatic hypertrophy. The specific
etiology regarding his chief symptom of
confusion is unclear and almost certainly
multifactorial.
References
1. Fung JJ, Alessiani M, Abu-Elmagd K, et al. Adverse effects
associated with the use of FK 506. Transplant Proc
1991;23(6):3105–8.
2. Alessiani M, Cillo U, Fung JJ, et al. Adverse effects of FK 506
overdosage after liver transplantation. Transplant Proc
1993;25(1):628–34.
3. Curran CF, Blahunka PC, Lawrence ID. Acute overdoses of
tacrolimus. Transplantation 1996;62(9):1376–7.
4. Yeh CN, Hsieh CH, Hung CM, Jeng LB, Chao TC, Chen MF.
Acute overdoses of tacrolimus (FK 506). Dig Dis Sci
1999;44(8);1650–2.
5. Mrvos R, Hodgman M, Krenzelok EP. Tacrolimus (FK 506)
overdose: a report of five cases. Clin Toxicol 1997;35(4):395–9.
6. Uchida N, Taniguchi S, Harada N, Shibuya T. Myocardial
ischemia following allogeneic bone marrow transplantation:
possible implication of tacrolimus overdose. Blood
2000;96(1):370–2.
7. Karasu Z, Gurakar A, Carlson J, et al. Acute tacrolimus
overdose and treatment with phenytoin in liver transplant
recipients. J Okla State Med Assoc 2001;94(4):121–3.
8. McLaughlin GE, Rossique-Gonzalez M, Gelman B, Kato T. Use
of phenobarbital in the management of acute tacrolimus toxicity:
a case report. Transplant Proc 2000;32:665–8.
Conclusion
Tacrolimus is a widely prescribed immuno-
suppressant administered for prevention of graft
rejection in organ transplant recipients. Long-
term administration of tacrolimus is associated
with numerous adverse effects. Acute overdose
of the drug, however, may exhibit minimal signs
and symptoms of toxicity. This absence of early
clinical manifestations of toxicity supports the