tacrolimus and Drug-Overdose

Posterior reversible encephalopathy syndrome is a neurotoxic state accompanied by unique brain imaging patterns and neurologic abnormalities, typically associated with several complex clinical conditions such as preeclampsia/eclampsia, solid-organ transplant procedures, autoimmune diseases, and immunosuppressive agents. The detailed mechanism of posterior reversible encephalopathy syndrome is not known, and the current therapy is only supportive care. Here, we present a 33-year-old parturient woman with preeclampsia complicated with hemolysis, elevated liver enzymes, and low platelet syndrome, fulminant hepatitis B, acute fatty liver, and posterior reversible encephalopathy syndrome. The patient developed gross hepatic infarction soon after liver transplant. After several possible causes were excluded, we found that progression of underlying posterior reversible encephalopathy syndrome-induced endothelial damage by overdose of tacrolimus may have been the major cause for deteriorating hypoperfusion of the transplanted liver and fatal graft failure. In liver transplant recipients, severe posttransplant hypoperfusion of the grafted liver may result in loss of the liver allograft and even mortality. Poor control of underlying posterior reversible encephalopathy syndrome-associated endothelial damage because of tacrolimus overdose may lead to severe hypoperfusion of grafted hepatic vessels and subsequent hepatic infarction. This report highlights tacrolimus as a potential trigger of posterior reversible encephalopathy syndrome and may inform clinical decisions regarding tacrolimus administration in liver transplant recipients with preexisting or newly developed posterior reversible encephalopathy syndrome.

Topics: Adult; Calcineurin Inhibitors; Disease Progression; Drug Overdose; Fatal Outcome; Female; Hepatic Infarction; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Multiple Organ Failure; Posterior Leukoencephalopathy Syndrome; Pregnancy; Tacrolimus

Immunosuppressive medication dosing errors are not unfrequent and may present a number of challenges to transplant clinicians. Tacrolimus (TAC) is a widely used immunosuppressant with a narrow therapeutic index and potential severe side effects, including neurotoxicity and kidney injury. We herein report a case of 60-year-old woman who underwent deceased-donor liver transplantation at our center and due to inadvertent TAC overexposure was admitted to the Intensive Care Unit because of severe neurologic impairment, kidney injury and arterial hypotension. This case was challenging because TAC is largely bound to erythrocytes, has a high molecular weight, is highly lipophilic, has a high distribution volume and cannot be removed by hemodialysis or plasmapheresis. Based on these considerations, we decided to replace TAC-saturated erythrocytes with blood-bank red cells with the aim to accelerate its clearance. The treatment was effective in decreasing TAC whole blood trough levels within the therapeutic ranges with a significant improvement of the patient's clinical status. Red-blood cell exchange is a potentially safe and effective means of managing severe and symptomatic TAC toxicity.

Topics: Cytapheresis; Drug Overdose; Erythrocyte Transfusion; Erythrocytes; Female; Humans; Middle Aged; Tacrolimus

Transplant recipients and other patients requiring immunosuppression with calcineurin inhibitors or their household contacts may be exposed to overdose. This study investigated the circumstances, pharmacokinetics and outcomes of overdose with cyclosporine and tacrolimus reported to the Swiss Toxicological Information Centre between 1995 and 2011. Of 145,396 reports by healthcare professionals, 28 (0.02%) concerned enteral or parenteral overdose with these calcineurin inhibitors. Thirteen (46%) were iatrogenic errors, 12 (43%) were with suicidal intent and 3 (11%) were accidental. Iatrogenic overdoses usually involved noncapsule drug formulations. Acute enteral overdoses caused symptoms in a dose-dependent fashion but were generally well tolerated; the mean multiple of patient's usual dose was 20.8 ± 28.8 for symptomatic versus 4.4 ± 3.4 for asymptomatic cases (p = 0.037). The most common symptoms were nausea, headache, somnolence, confusion, hypertension and renal impairment. In contrast, acute intravenous overdoses were often poorly tolerated and resulted in one fatality due to cerebral edema after a cyclosporine overdose. Enteral decontamination measures were performed in six cases involving oral ingestion and appeared to reduce drug absorption, as shown by pharmacokinetic calculations. In the one case where it was used, pharmacoenhancement appeared to accelerate tacrolimus clearance after intravenous overdose.

Topics: Acute Disease; Adolescent; Adult; Aged; Ambulatory Care; Calcineurin Inhibitors; Child; Child, Preschool; Cyclosporine; Decontamination; Drug Overdose; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Male; Middle Aged; Poison Control Centers; Prognosis; Retrospective Studies; Risk Factors; Switzerland; Tacrolimus; Time Factors; Tissue Distribution; Young Adult

Topics: Acute Disease; Child, Preschool; Drug Overdose; Ecchymosis; Female; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Recurrence; Tacrolimus

Topics: Citrus paradisi; Drug Overdose; Food-Drug Interactions; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Tacrolimus

A case of a 23-year-old female, after renal transplant, who had tried to commit suicide with 100 mg of Prograf was described. In the presented case despite the relatively high tacrolimus blood concentration level (>30 microg/l) only severe 5-hour lasting headache and short-term mild hyperglycaemia (7.22 mmol/l), hyperkalemia (5.4 mmol/l) and considerable leukocytosis (19.52 x 10(3)) were observed. In this case there was mild clinical course of intoxication despite tacrolimus high blood concentration. It could not be excluded that early administration of gastric lavage and activated carbon was partly responsible for mild course of poisoning.

Topics: Acute Disease; Adult; Charcoal; Depression; Drug Overdose; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Poisoning; Suicide, Attempted; Tacrolimus; Time Factors; Treatment Outcome

Acute overdose of tacrolimus appears to cause no or minimal adverse clinical consequences. We encountered a pediatric case who underwent liver transplantation associated with hepatic artery thrombosis (HAT), which recurred following acute tacrolimus overdose. A 10-month-old girl underwent living-related liver transplantation because of biliary atresia. To reconstruct the hepatic artery, the right gastroepiploic artery of the donor was interposed between the right hepatic artery of the recipient (2.5 mm in diameter) and the left hepatic graft artery (1 mm in diameter) under microscopy. On postoperative day 4, Doppler ultrasonography showed a remarkable reduction in hepatic arterial flow, which was consistent with HAT. The patient underwent immediate hepatic arteriography and balloon angioplasty. The stenotic sites were dilated by the procedure. Tacrolimus was infused intravenously after transplantation and the infusion rate was adjusted to achieve a target concentration of 18-22 ng/mL, which remained stable until the morning of day 6. An unexpectedly high blood concentration of tacrolimus (57.4 ng/mL) was detected at 6:00 PM on day 6, and tacrolimus was discontinued at 9:00 PM; however, the tacrolimus level reached 119.5 ng/mL at 0:00 h on day 7. While the concentration decreased to 55.2 ng/mL on the morning of day 7, the hepatic arterial flow could not be observed by Doppler ultrasonography. Emergent hepatic arteriography showed stenosis of the artery at the proximal site of the anastomosis. Balloon angioplasty was again performed and the stenotic site was successfully dilated. High level of tacrolimus exposure to the hepatic artery with injured endothelium by preceding angioplasty may have been related to the recurrence of HAT in the present case.

Topics: Blood Urea Nitrogen; Child; Cholangitis; Creatinine; Drainage; Drug Monitoring; Drug Overdose; Female; Hepatic Artery; Humans; Immunosuppressive Agents; Infusions, Intravenous; Liver Transplantation; Postoperative Complications; Recurrence; Tacrolimus; Thrombosis; Treatment Outcome; Ultrasonography

Topics: Adult; Drug Overdose; Female; Humans; Immunosuppressive Agents; Tacrolimus

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.

Topics: Diabetic Nephropathies; Drug Labeling; Drug Overdose; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Patient Education as Topic; Tacrolimus

As a potent immunosuppressive agent, Tacrolimus is widely used in organ transplantation. Although complications due to chronic Tacrolimus use are rather well recognized, little is known about acute overdose and its treatment. Phenytoin, an anti-convulsant agent, can induce the Cytochrome P450 enzyme in the liver, which metabolizes Tacrolimus. Therefore, it can be considered as a potential treatment option for acute Tacrolimus toxicity. We hereby report two cases of acute Tacrolimus overdose after Orthotopic Liver Transplantation and the treatment with Phenytoin. Probable mechanisms of metabolism and interactions of these two drugs are discussed and the literature is reviewed.

Topics: Child, Preschool; Drug Overdose; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Tacrolimus

FK506-induced polyneuropathies are rarely encountered. We report a case of axonal sensorimotor polyneuropathy in a lung transplant recipient that occurred during a FK506 overdosage. Onset was acute in the form of severe areflexic tetraparesis and resolution was observed after reduction of dosage. Because of increasing use of FK506 in solid organ transplantation, caution should be paid with FK506 dosage monitoring in cases of peripheral nervous system symptoms.

Topics: Dose-Response Relationship, Drug; Drug Overdose; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Polyneuropathies; Quadriplegia; Tacrolimus

Topics: Adult; Drug Overdose; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Medication Errors; Postoperative Care; Tacrolimus

Tacrolimus (FK 506), a potent anti-T cell agent, has been shown to be effective in preventing the rejection of transplanted organs. Published research on tacrolimus has focused on effects associated with therapeutic use. Virtually no literature addresses the acute toxicity or the management of tacrolimus overdose. We report five cases of acute overdose with tacrolimus.. A 2-year-old female with no prior medical history ingested 10 mg of tacrolimus. She remained asymptomatic. A 2-year-old female with a history of multiple visceral organ transplants ingested 11 mg of her tacrolimus. She was admitted to the hospital and activated charcoal was administered. Her renal function was monitored and no changes were noted in a 24 h period. She was discharged. A 29-year-old male renal transplant patient took 150 mg of tacrolimus. He recovered with only a minimal creatinine elevation. A 23-year-old heart and lung transplant patient ingested 375 mg of tacrolimus. She had no effects from the overdose. A 34-year-old female experienced an acute/chronic overdose of 7-9 mg and remained asymptomatic.. Tacrolimus is a neutral macrolide antibiotic that is extracted from the fermentation broth of the soil fungus Streptomyces tsukubaensis. Chronic oral dosing has been associated with numerous side effects. Although these patients ingested significant doses of tacrolimus, they suffered few toxic manifestations associated with tacrolimus.. Little information is available regarding acute tacrolimus overdosage. In this small series of patients, tacrolimus did not produce acute physiologic incapacitation.

Topics: Adult; Anti-Bacterial Agents; Charcoal; Child, Preschool; Drug Overdose; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus

Topics: Adolescent; Adult; Child; Child, Preschool; Drug Overdose; Humans; Immunosuppressive Agents; Infant; Tacrolimus