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Keywords:

  • Calcineurin inhibitor;
  • decontamination;
  • overdose;
  • toxicity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Supporting Information

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.


Abbreviations
CNI

calcineurin inhibitor

CSA

cyclosporine

f

female

m

male

n

no

SD

standard deviation

STIC

Swiss Toxicological Information Centre

TAC

tacrolimus

y

yes

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Supporting Information

Transplant recipients and other patients requiring immunosuppression with calcineurin inhibitors (CNIs) or their household contacts may be intentionally or unintentionally exposed to an overdose of these substances. The published information regarding CNI overdose consists of 24 case reports and two case series [1, 2]. A case series of cyclosporine (CSA) overdoses examined 18 cases reported to a single center prior to 1991 and nine case reports published in the medical literature between 1985 and 1989. This historical cohort included five overdoses via the intramuscular route—a route of administration which is no longer used [1]. The five tacrolimus (TAC) cases from a single center were reported prior to 1997 and all involved oral administration [2]. Neither report addressed the effect of gastrointestinal decontamination following oral ingestion or pharmacoenhancement (induction of drug metabolism to enhance clearance) after intravenous administration. The optimal management of CNI overdose has not yet been identified.

The purpose of this study was to investigate the circumstances, pharmacokinetics and outcomes of overdoses with CSA and TAC in the current era using data reported to a single national poison center.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Supporting Information

Study design

We performed a retrospective review of acute overdoses involving CNIs either alone or in combination with other drugs in adults and children (<16 years) that had been reported to the Swiss Toxicological Information Centre (STIC) between April 1995 and December 2011 (for further details, please see the online supplement).

Circumstances and symptoms of overdose

The circumstances of overdose were categorized as “suicidal intent” for cases of intentional overdose, “accidental, domestic” for cases of unintentional overdose in the home (primarily in children) and “accidental, iatrogenic” for those due to a prescribing or administration error in hospital.

The severity of symptoms were graded in accordance with the Poisoning Severity Score (PSS) as “minor”, for mild, transient and spontaneously resolving symptoms/signs; “moderate”, if at least one pronounced or prolonged symptom/sign was recorded; “severe”, if at least one severe or life-threatening symptom/sign was observed, or “fatal”, if the overdose was the recorded cause of death [3].

Cases were assessed for association between symptoms and the overdose by an expert panel including a clinical pharmacologist and a clinical toxicologist, both with additional qualifications in general internal medicine, using the World Health Organisation Uppsala Monitoring Centre (WHO-UMC) standardized case causality assessment criteria [4]; comorbidities, coingestion of other medication and the magnitude of overdose were taken into consideration. Associations were classified as “certain”, “likely”, “possible” and “unlikely” (Table S1).

Statistical and pharmacokinetic analyses

Descriptive statistics were used to analyze grouped data. Overdoses in mg/kg were compared with usual therapeutic doses by determining the multiple of the subject's usual therapeutic dose (dose received/usual dose). In subjects who did not normally receive a CNI or in cases where the usual maintenance dose was unknown, the magnitude of overdose above the maximum licensed dose was determined. In Switzerland the maximum licensed doses for oral and intravenous CSA are 15 mg/kg/day and 5 mg/kg/day respectively, and for oral TAC 0.3 mg/kg/day [5][7]. The Mann–Whitney U-test was performed to test for dose dependence of symptoms. Missing data regarding patient weight was computed as detailed in the online Supporting Information. Odds ratios were determined for the association between iatrogenic overdoses and subsequent active management steps undertaken. Analyses were performed using the statistical software package VassarStats, Vassar College, Poughkeepsie, NY, USA (http://www.vassarstats.net/). Pharmacokinetic calculations were performed using standard equations (see Supporting Information).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Supporting Information

There were a total of 145 396 reports of confirmed or suspected overdose with any substance by healthcare professionals during the study period 1995–2011. Of these, 28 (0.02%) concerned enteral or parenteral overdose with CNIs in subjects aged 2 months to 75 years.

Table 1 shows the subjects' characteristics and the circumstances of overdose. Twenty CSA and eight TAC overdoses were reported. The majority were reported by hospital doctors (n = 24), the remainder by family doctors. Twenty-two cases (79%) involved patients already receiving immunosuppression, five (18%) involved household contacts of CNI-treated patients and in one case the source of the CNI was unknown. Thirteen (46%) were iatrogenic errors, 12 (43%) were with suicidal intent (10 involving multiple drugs) and three (11%) were accidental, occurring at home (Table 1). Among the iatrogenic cases, five were due to errors in the calculation or administration of an oral liquid formulation (particularly via a nasogastric tube) and four were due to errors in the calculation or administration of intravenous infusions; 70% of iatrogenic errors therefore involved noncapsule drug formulations.

Table 1. Patient demographics, circumstances of overdose and overdose amount
PatientAge (years)SexWeight (kg)Underlying conditionCircumstance of overdoseMono- intoxicationDrugDose (mg/kg)Subject's usual dose (mg/kg/12 h if oral or mg/kg/day if i.v.)
  1. m = male, f = female, y = yes, n = no, uk = unknown. Oral CSA overdoses were with Sandimmun Neoral® unless otherwise stated.

  2. *Subacute overdose: erroneously high dose administered daily for 4 days.

151mukLung transplantAccidental iatrogenicYCSA intravenous solution5.620.56
218f42Bone marrow transplantAccidental iatrogenicYCSA intravenous solution3.572.5
30.4m5Unknown condition requiring immunosuppressionAccidental iatrogenicYCSA oral solution (Sandimmun®)12.001.20
430f57Heart transplantAccidental iatrogenicYCSA oral solution5.261.49
53m12Renal transplantAccidental domesticYCSA oral solution20.832.08
671mukHeart transplantAccidental iatrogenicYCSA oral solution7.200.72
74m18Bone marrow transplantAccidental domesticYCSA oral solution16.71.67
80.2f3.8Hemophagocytic lymphohistiocytosisAccidental iatrogenicYCSA oral solution315.83.16
90.5m6Heart transplantAccidental iatrogenicYCSA oral solution50.03.3
1020f65ALL, bone marrow transplant, GVHDSuicidal intentNCSA capsules (exact formulation uk)76.921.85
1155m85Diabetes, hypertension (access to immunosuppression not known)Suicidal intentNCSA capsules29.41Unknown
1239f50Heart transplantSuicidal intentNCSA capsules16.00Unknown
13adultmukUnknown condition requiring immunosuppressionSuicidal intentYCSA capsules5× usualUnknown
1452f52SclerodermaSuicidal intentNCSA capsules2.881.44
1524f48HIV—treatment unknown (cohabitant of a renal transplant patient)Suicidal intentNCSA capsules5.70
1615m44Lung transplantAccidental iatrogenicYCSA capsules12.271.82
1716f46None (cohabitant of a CSA-user)Suicidal intentYCSA capsules4.350
1839fukHIV treated with ritonavir (access to immunosuppression not known)Suicidal intentNCSA capsules4.480
1975fukRenal transplant, diabetes mellitusSuicidal intentNCSA capsules8.062.69
2019fukSystemic lupus erythematosusSuicidal intentNCSA capsules48.41.79
219.5f33.5Bone marrow transplantAccidental iatrogenicYTAC intravenous solution0.190.019
229f26Bone marrow transplant, GVHDAccidental iatrogenicYTAC intravenous solution2.000.08
233.5m14Liver transplantAccidental iatrogenicYTAC capsules0.640.07
24adultmukRenal transplantSuicidal intentNTAC capsules0.12Unknown
252.5f15.5None (cohabitant of a TAC-user)Accidental domesticNTAC capsules0.190
2612f39None (cohabitant of a TAC-user)Suicidal intentNTAC capsules0.260
2770m53Bone marrow transplant, GVHDAccidental iatrogenic*YTAC capsules0.140.014
2869m60Liver transplantAccidental iatrogenic*YTAC capsulesunknownunknown

Magnitude of overdose

All cases involved exposure to a CNI dose which exceeded the usual dose for the subject reported by the healthcare professional (Table 1). In patients receiving CNIs regularly, overdoses ranged from 1.4- to 100-fold above their usual dose. In 10 cases the degree of overdose above the maximum licensed dose had to be determined either because the patients were CSA- or TAC-naive (n = 5) or the patient's usual maintenance dose was not known (n = 5). Four of the exposures were less than the maximum licensed dose, three being in treatment-naive individuals.

Outcome of CSA overdose

Half of the CSA overdoses were judged to have caused or contributed to symptoms or abnormal clinical findings (Table 2). Of these, seven were minor, one moderate, one severe and one fatal. There was one occurrence each of headache, confusion, agitation, transient renal impairment, somnolence, epileptic seizure and cerebral edema and two occurrences of a transient rise in blood pressure. The fatal and severe cases (cerebral edema and seizures, respectively) both occurred after intravenous drug administration. The fatality due to cerebral edema occurred after an intravenous CSA overdose of 10 times greater than intended over a period of 13 h and has been reported previously [8]. Thus, both cases of intravenous CSA overdose developed symptoms compared to less than half of oral overdoses (eight of 18).

Table 2. Overdosage as a multiple of the patient's usual dose (or factor above maximum licensed dose), maximal measured blood concentrations, decontamination measures and clinical findings
PatientMultiple of usual or maximum licensed dose1Measured blood concentrations (ng/mL) (time postoverdose h)Decontamination measuresClinical findingsSeverityRelatedness to overdose
  1. 1Per 12 h if oral or per 24 h if i.v.

  2. 2Maximal licensed dose of oral CSA in Switzerland is 15 mg/kg/day.

  3. 3Cotherapy with ritonavir—a potent cytochrome 3A4 inhibitor which reduces the clearance of CSA. The ingested dose is therefore likely to have caused a whole-blood CSA concentration which was much higher than the usual target concentrations in individuals receiving CSA for therapeutic purposes.

  4. 4Maximal licensed dose of oral TAC in Switzerland is 0.3 mg/kg/day.

  5. 5Unknown.

Intravenous CSA overdoses     
1101256 (after 7 h of adverse infusion)NoneMydriasis 3 h postoverdose, CT-confirmed diffuse cerebral oedema, massive intracranial hypertension (up to 100 mmHg) and death approximately 12 h after cessation of intravenous CSAFatalCertain
21.4500 (unknown time postdose)—described by reporter as “high”NoneTwo generalized tonic-clonic seizures within 0.5 h. Responded to phenobarbital i.v.SevereCertain
Oral CSA overdoses     
310374 (unknown time postoverdose)DimeticonAsymptomatic 3 h postoverdose  
  29 (60)    
43.53“Therapeutic” (8)Nasogastric tube aspiration 10 minutes after overdoseNasogastric tube aspiration 10 minutes after overdose  
510Not availableNoneAsymptomatic at 12 h postoverdose  
610Not availableNoneConfusion and agitation 10 h postoverdoseModerateLikely
7101500 (immediately postoverdose)NoneTransient renal impairment: Cystatin C 1.36 mg/L (upper limit of normal <0.95) within 72 days of overdoseMinorLikely
  789 (24)    
  296 (48)    
8100836 (15)Nasogastric tube aspiration immediately after overdoseTransient rise in systolic blood pressureMinorLikely
  408 (39)    
915750 (8)Single dose activated charcoal 6 gNausea (unknown time after overdose)MinorCertain
1041.58>3000 (5)Single dose activated charcoal 15 gCerebral depression within 5 h of overdoseMinorPossible
  500 (24)    
113.92Not availableSingle dose activated charcoal 90 gRise in blood pressure (unknown time after overdose)MinorPossible
122.132Not availableNoneAsymptomatic up to 5 120 h postoverdose  
135Not availableNoneAsymptomatic 5 h postoverdose  
142Not availableNoneVomiting ×1 “a few” h postoverdoseMinorUnlikely—concomitant codeine overdose likely cause
150.76Not availableNoneVomiting and mild abdominal pain 3 h postoverdoseMinorUnlikely—concomitant mycophenolate overdose likely cause
166.741395 (3)NoneAsymptomatic 6 h postoverdose. Normal renal function  
170.58Not availableNoneAsymptomatic up to 24 h after overdose  
180.63Not availableNoneHeadache within 4 h of overdoseMinorPossible
193Not availableNoneAsymptomatic  
2027Not availableNoneSomnolence 2 h after overdoseMinorPossible
Intravenous TAC overdoses     
211039.6 (immediately postoverdose)NoneHeadache, nausea, abdominal cramps for 15 h after stopping infusionMinorCertain
  18.8 (9)    
  15.8 (17)    
  9.8 (33)    
2225>90 (immediately postoverdose),Pharmacoenhan cementAsymptomatic up to 288 h postoverdose  
  120 (12)    
  64.2 (24)    
  18.2 (48)    
  6.4 (72)    
Oral TAC overdoses     
239.1411 (24)Single dose activated charcoal 6 gInitial ventricular repolarization disturbance on ECG. Asymptomatic at 24 h. Renal and liver function tests normal 144 h postoverdoseMinorLikely
240.84Not availableNoneSomnolence (unknown time postoverdose); ECG normalMinorUnlikely—concomitant valproic acid overdose likely cause
251.3Not availableNoneSomnolence 3 h after ingestionMinorUnlikely—concomitant levetiracetam ingestion likely cause
261.7328.5 (24)NoneHeadache and abdominal pain within 3 h of overdoseMinorPossible
2710>90 (unknown time postoverdose)NoneCoarse tremor, bilateral mydriasis, encephalopathy (confusion and aphasia), worsening renal function within 120 h of the start of overdose. Slow improvement after 4 days and no lasting deficits at 3 weeks postoverdoseSevereCertain
28534 (unknown)30 (unknown)NoneTremor, encephalopathy (agitation and confusion), extrapyramidal symptoms and worsening renal function. Normalization of TAC blood levels resulted in symptom resolutionSevereLikely

Outcome of TAC overdoses

Of the eight TAC overdoses, five developed symptoms or signs (three minor, two severe). Minor symptoms were two cases of abdominal pain with headache and one case each of nausea and nonspecific ECG repolarization changes. Severe symptoms were seen in both cases of subacute overdose caused by iatrogenic error and were tremor, encephalopathy and worsening renal function. Of the two intravenous overdoses, one was asymptomatic and the other showed only minor symptoms (Table 2).

Factors associated with the development of symptoms

In cases of oral overdose there was a significant association between the magnitude of overdose as measured by the multiple of the usual dose administered or maximum licensed dose and the development of symptoms with a mean multiple of 20.8 ± 28.8 for symptomatic compared to 4.4 ± 3.4 for asymptomatic cases (p = 0.037). There was no association between age and the development of symptoms (p = 0.24).

Management

Fourteen of the 16 out of hospital overdoses resulted in hospital admission. Discontinuation of CSA or TAC until therapeutic trough concentrations were measured and symptom management (if required) were recommended in all cases. The use of decontamination measures is shown in Figure 1. Phenobarbital was administered in one case to treat CSA-induced seizures and for pharmacoenhancement alone in one case of intravenous TAC overdose. Active measures were more likely to be undertaken if the cause of the overdose was iatrogenic (OR 7.58, 95% confidence interval 1.2–48). The mean multiple of the usual or licensed dose among patients who underwent decontamination with activated charcoal or nasogastric tube aspiration or pharmacoenhancement was 28.9 ± 33.2 versus 6.4 ± 6.4 (p = 0.012) among patients who did not undergo decontamination.

image

Figure 1. Decontamination measures undertaken. Figures in brackets refer to absolute numbers. CSA = cyclosporine; TAC = tacrolimus.

Download figure to PowerPoint

Pharmacoenhancement

Serial whole-blood concentration measurements enabled the calculation of half-lives in five cases (Table S2). Patient 22, who received a 25-fold TAC overdose, underwent pharmacoenhancement with intravenous phenobarbital and dexamethasone. The mean half-life calculated from four serial postdistributional whole-blood concentration measurements was 14.1 h. This is in contrast to 27.5 h which was the mean half-life determined from three postdistributional serial measurements in patient 21, who did not undergo pharmacoenhancement. Both patients were of similar age and weight (Table 1).

Effect of decontamination

It was possible to estimate the dose of CNI which would have been required to achieve the measured whole-blood concentration in eight cases of oral CNI overdose (Table 3). A ratio of the actual dose to the estimated dose ingested was then calculated to give an indication of the proportion of drug that was absorbed (a ratio of 1 corresponding to complete absorption and >1 to incomplete absorption). Patients who did not undergo decontamination with activated charcoal or aspiration of an in situ nasogastric tube had near complete drug absorption whereas those who underwent decontamination did not (Table 3).

Table 3. Theoretical doses required to achieve the measured whole blood concentration compared to actual doses ingested in order to determine the effect of active decontamination
PatientAge (years)DrugDose (mg/kg)Measured concentration (ng/mL) (hours postdose)Dose required to achieve this blood concentration (mg/kg)Ratio of ingested dose required to achieve measured blood concentrationDecontamination
  1. 1Or 6.94 if the Tmax and bioavailability of Sandimmune® is used in the calculations.

  2. 2Dimeticon is an antiflatulent. The patient may have received a combination formulation of dimeticon and activated charcoal (Carboticon®, Interdelta SA, Fribourg, Switzerland).

74CSA16.71500 (0)11.661.43None
1615CSA12.31393 (3)11.181.10None
2612TAC0.2628.5 (24)0.221.18None
90.5CSA50.0750 (8)7.057.10Charcoal
1020CSA76.9500 (24)7.779.901Charcoal
233.5TAC0.6411 (24)0.292.16Charcoal
80.2CSA315.8836 (15)9.6232.8Nasogastric tube aspiration immediately after overdose
30.4CSA12.029 (60)1.45.98Dimeticon2

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Supporting Information

In this retrospective analysis of CNI overdoses reported to a single poison center between 1995 and 2011 we found that acute overdoses with CNIs are rare but can be associated with an unfavorable outcome. This study confirms a number of the findings of a previous study of CSA overdose reported more than 20 years ago [1] and a case series of TAC overdoses reported 16 years ago [2], but also describes differences which are likely due to the diverse eras in which the studies were carried out.

Three important issues emerge when examining the circumstances of overdose with CNIs. First, the high number of iatrogenic overdoses involving noncapsule formulations which was also found by Arellano and colleagues [1] highlights the fact that extra vigilance is required by healthcare staff when dealing with these formulations and when switching from one dosage form to another [9]. Second, CSA overdose with suicidal intent was more prevalent in our cohort (50%) than in the earlier report by Arellano (15%), indicating an increase in more recent years [1]. Intentional CNI overdose in transplant patients deserves particular attention, since depression—with the inherent risk of suicidal behavior—is prevalent in the early period after transplantation [10]. Third, in the two previously published case series [1, 2], only two patients out of the total 32 were over the age of 48, compared to seven out of 28 in our study, which likely reflects the increased long-term survival of patients taking immunosuppressants and transplantation in older adults.

Oral CSA overdoses were reported to have a low acute toxicity resulting in minimal symptoms (including nausea, vomiting, headache, tachycardia, hypertension, drowsiness) and/or mild renal dysfunction in half of the cases [1]. Parenteral overdoses (intravenous or intramuscular) however were associated with metabolic acidosis, cyanosis, worsening renal function, hyponatremia and oliguria. Of note, the majority of these cases were in premature infants and infants under 45 days old who are known to have reduced hepatic drug-metabolizing capacity [11]. Our data did not include similar cases, but did include a case of fatal intravenous overdose in an adult. Overdose of intravenous TAC have previously also been reported to be more toxic than enteral overdose [2, 12, 13]. Taken together with our findings, these observations suggest that excessively high blood concentrations over several hours are more likely to cause significant toxicity than a short-lived high peak concentration following a single oral ingestion. However, the effect of a significant oral overdose should not be underestimated for several reasons. First, symptoms classified as “minor” according to the PSS may still cause discomfort and distress to the patient. Second, one patient in our study developed “moderate” symptoms of confusion and agitation and there is evidence from other reports that acute, one-time CSA overdoses via the enteral route can have clinically significant effects [14, 15]. Third, our data suggest that the occurrence of symptoms is dose dependent. Last, the long-term effects of short exposure to excessive CNI concentrations are not known.

The use of gastrointestinal decontamination measures in the management of oral CNI overdose was more frequent in the two previous reports than in our study. In the case series reported by Arellano and colleagues, 10 of 21 (48%) oral CSA overdoses received such treatment [1] compared with five of the 18 (28%) cases of oral CSA overdose reported here. Two of the five cases (40%) of oral TAC overdose reported by Mrvos and colleagues received activated charcoal, compared with one of the six (17%) of our cases.

Due to the rarity of CNI overdose, it is not possible to perform randomized controlled trials to determine its optimal management and examination of case data remains the only option. The role of activated charcoal in the management of oral CNI overdose is currently uncertain; in the past, some have advocated its use in CSA overdose [16, 17] while others have not [1]. Data regarding its use in TAC overdose are sparse. Arellano and colleagues based their recommendation not to use activated charcoal on theoretical considerations regarding the poor efficacy of CSA adsorption to charcoal and potential hazards associated with its use and not on clinical data. They recommended gastric lavage or induced emesis within 6 h of overdose only for patients “previously not healthy”, “previously receiving CSA” and those “without stable renal function” [1]. The data we found in our study have led us to question this recommendation for several reasons. First, induced emesis is risky and it is no longer recommended in the treatment of enteral overdose. Second, by pharmacokinetic calculation, we found that activated charcoal appears to be effective in reducing drug absorption. Third, neither our data nor that from any previously reported cases showed activated charcoal to be associated with adverse effects in the setting of CNI overdose. We therefore suggest that activated charcoal may be effective in the management of enteral CNI overdoses when there is a risk of serious toxicity due to the magnitude of the dose ingested.

Acceleration of drug clearance by pharmacoenhancement through induction of CYP 3A activity by coadministration of phenytoin or phenobarbital has previously been shown to reduce the half-lives of both CSA and TAC and possibly prevent seizures [18-20]. Data regarding the efficacy of dexamethasone combined with phenobarbital for pharmacoenhancement (used in the case we describe) are lacking. Dexamethasone is a weak CYP 3A inducer and we suspect it did not play a significant role in accelerating hepatic drug clearance in this case. However, as the patient had been receiving methylprednisolone as part of her immunosuppressive regime, a temporary switch to a steroid with CYP-inducing activity such as dexamethasone could potentially have been of benefit in this context. Our data, although limited to two cases, support the efficacy of pharmacoenhancement in enhancing TAC clearance. On the balance of current evidence and in light of the minimal associated risks, we believe pharmacoenhancement could be considered in the management of intravenous CNI overdose, while recognizing the lack of data from randomized trials.

Our study has a number of limitations, primarily related to the small sample size. Larger single-center series of CNI overdoses have, however, not been published and the previous data are more than 20 years old. It is likely that our data did not capture all cases of CNI overdose which occurred in the referral population and that bias toward reporting of the more severe cases occurred. Our data are also incomplete, which is the nature of retrospective studies using poison center data [21]. The use of population data to substitute for missing data in the determination of the amount of drug absorbed is a clear, but unavoidable, limitation. Furthermore, inaccuracy of dose information in some cases cannot be excluded, although dose information has been found to be accurate in other similar studies [22, 23]. The bioavailability of CNIs is known to show large inter- and intraindividual variability, however determination of individual bioavailability was clearly not possible. Laboratory analytical methods for determining CSA and TAC blood concentrations may have differed between hospitals and over time.

In conclusion, acute toxicity with CNIs appears to be significant when exposure to high drug levels persists for some time. Gastrointestinal decontamination with activated charcoal or aspiration of an in situ nasogastric tube appears to reduce CNI absorption and should be considered in cases of large enteral overdose. In addition, our data highlight that prescribing physicians should take extra care to avoid iatrogenic overdoses when using noncapsule drug formulations. CNI overdose patterns, outcomes and management require continued study and transplant and poison centers globally should be encouraged to actively seek follow-up data on the cases of CNI overdose with which they are involved.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Supporting Information

Funding was through internal funds of STIC and University Hospital Basel. M.A. is supported by grants from CANSEARCH and Hans Wilsdorf foundations. S.K. is supported by grants from the Swiss National Science Foundation (SNF31003A-132992).

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Supporting Information

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
  10. Supporting Information

Disclaimer: Supplementary materials have been peer-reviewed but not copyedited.

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ajt4347-sup-0001-TableS1.doc73K

Supporting Materials and Methods

Table S1: World Health Organisation Uppsala Monitoring Centre (WHO-UMC) causality categories (Ref. S7)

Table S2: Calculated half-lives in patients for whom serial whole blood concentration measurements were available

Supplemental References

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