Acute cyclosporine overdose: A systematic review

Abstract

Context

Cyclosporine is the first drug to revolutionize organ transplantation; this drug was approved for autoimmune and graft versus host disease (GVHD) treatment. Based on case reports, Cyclosporine overdose has morbidities (including acute renal failure (ARF), seizure, coma, hepatitis, and neurologic disorder) and mortality.

Background

Although cyclosporine was discovered many years ago and is still used to treat many diseases, its narrow therapeutic index can cause significant problems.

Methods

We performed a literature search across three databases, including Medline, EMBASE, and Science Direct, and reviewed statistical sources from January 1, 1983, to April 31, 2020. Papers were eligible for what they described, either acute or acute chronic cyclosporine overdose. At least one serum cyclosporine concentration had to be reported for inclusion. Reports on chronic poisoning, studies on side effects of therapeutic drug uses, and animal studies were excluded.

Results

We found 81 cases from 37 articles that met inclusion criteria, potentially life-treating symptom coma (10%), seizure (16%), cardiac tachycardia (3%), and death (5%). Pediatrics are more susceptible to cyclosporine overdose, treatment interventions like gastric lavage (6.3%), charcoal administration (6.3%), whole blood exchange (5%), a huge overdose of more than 400 mg/kg oral route, or serum levels of more than > 3800 ng/ml related to death, seizure associated with upper threshold level > 500 ng/ml and coma related to the upper level of 1000 ng/ml cyclosporine levels, charcoal administration, and whole blood exchange reduce cyclosporine level and cure the patients.

Conclusions

Fifty percent of patients showed no or minimum toxicity and fifty percent showed severe signs and symptoms of poisoning. Almost all patients have a good outcome if cyclosporine overdose is diagnosed and treated on time.

Resumen

Contexto

La ciclosporina es el primer fármaco que revolucionó el trasplante de órganos; este fármaco está aprobado para el tratamiento de la enfermedad autoinmune y de injerto contra huésped (EICH). Según los informes de casos, la sobredosis de ciclosporina tiene morbilidades (que incluyen insuficiencia renal aguda (IRA), convulsiones, coma, hepatitis y trastornos neurológicos) y mortalidad.

Antecedentes

Aunque la ciclosporina se descubrió hace muchos años y todavía se usa para tratar muchas enfermedades, su estrecho índice terapéutico puede causar problemas importantes.

Métodos

Realizamos una búsqueda bibliográfica en tres bases de datos, incluidas Medline, EMBASE y Science Direct, y revisamos fuentes estadísticas desde el 1 de enero de 1983 hasta el 31 de abril de 2020. Los artículos eran elegibles por lo que describían, sobredosis de ciclosporina aguda o crónica aguda. Se tuvo que informar al menos una concentración de ciclosporina sérica para su inclusión. Se excluyeron los informes sobre intoxicaciones crónicas, los estudios sobre los efectos secundarios del uso de fármacos terapéuticos y los estudios con animales.

Resultados

Encontramos 81 casos de 37 artículos que cumplían con los criterios de inclusión, coma sintomático de tratamiento potencialmente vital (10 %), convulsiones (16 %), taquicardia cardíaca (3 %) y muerte (5 %). Los pediátricos son más susceptibles a la sobredosis de ciclosporina, las intervenciones de tratamiento como el lavado gástrico (6,3 %), la administración de carbón (5 %), el intercambio de sangre total (5 %), una sobredosis enorme de más de 400 mg/kg por vía oral o los niveles séricos de más de > 3800 ng/ml relacionado con la muerte, convulsiones asociadas con el nivel de umbral superior > 500 ng/ml y coma relacionado con el nivel superior de 1000 ng/ml niveles de ciclosporina, administración de carbón y recambio de sangre total reducen el nivel de ciclosporina y curan el paciente.

Conclusiones

El 50% de los pacientes presentó toxicidad nula o mínima y el 50% presentó signos y síntomas severos de intoxicación. Casi todos los pacientes tienen un buen resultado si la sobredosis de ciclosporina se diagnostica y trata a tiempo.

Introduction

The discovery of Cyclosporine as an Immunosuppressive agent opened new horizons in medicine. Cyclosporine (C62H111N11O12) is a family of structurally fungal antibiotic peptides with 11 amino acids isolated from the fungi Tolypocladium inflatum Gams in 1970 by Borel et al.,¹ in the laboratories of the Sandoz Company. The compound is neutral, with a molecular weight of 1203 Dalton, full of hydrophobic amino acids, insoluble in water and saturated Carbohydrates, highly soluble in all other organic solvents, and exceedingly difficult to crystallize. Purified Cyclosporine appears as white prismatic needles. Cyclosporine primary immunosuppressive agent with unique anti-lymphocyte activity was used in animal transplantation in the laboratory. After that, Calne began clinical trials in 1977 using Cyclosporine for cadaveric renal allograft recipients.^2,3

Many renal and hematologic transplantation centers using this agent as a primary drug of immunosuppressive therapy rapidly increased over three decades and have been used in other organ transplants and treatment of immunologic and autoimmune diseases and cancers.⁴

Cyclosporine suppresses the immune response in two pathways: calcineurin-dependent and calcineurin-independent. Cyclosporine exerts its cellular effects by binding to proteins called cyclophilin-A (immunophilins). The cyclosporine-cyclophilin_A complex joins with calcineurin preventing its binding and activation of nuclear factor-associated transcriptase (NFAT) (NFAT and activated protein kinases_1 (AP-1) are Necessary to Activate T cells).⁴ Cyclosporine suppresses the immune response in the Non-dependent calcineurin pathway. It has been shown to block both the Jun N terminal kinase and p38 signaling pathways, these pathways are necessary to activate AP-1, among other transcription factors. Cyclosporine is associated with the up-regulation of transforming growth factor-beta (TGF-beta). This cytokine has significant immunosuppressive properties but also promotes the deposition of matrix proteins and the development of tissue fibrosis.^5,6

Cyclosporine has highly variable and difficult to predict bioavailability. The pharmacokinetic properties of Cyclosporine can be significantly influenced by age, ethnicity, gastrointestinal conditions, and disease.⁷ Cyclosporine has an exclusive fungus Amino acid structure and P-glycoprotein poorly absorbed from intestines. Following oral administration, the absorption of Cyclosporine is slow, erratic, and incomplete.⁶ Cyclosporine absorption has zero-order kinetics. Cyclosporine may be given parenterally or orally. Absorption of Cyclosporine from GI takes 1.5 to 2 hours. Peak serum concentrations in patients receiving overdoses of cyclosporine have been achieved as late as 2 to 5 h after the ingestion of the drug (average 6 h).⁵

First, the bioavailability of the oil-based formulation cyclosporine (Sandimmune) ranged from 1% to 89%, with a mean value of 30%. Cyclosporine microemulsion preparation (Neoral) led to enhanced bioavailability and more independence from bile secretion. Neoral absorption is faster reaching to maximum level.⁷ The correlation between the drug dose usage and AUC for Neoral was higher than for Sandimmune. Further, interpatient variability in cyclosporine pharmacokinetics for the microemulsion (Neoral) was lower than the oil preparation (Sandimmune).⁷

Cyclosporine Vd varies between 4 and 8 L/kg and can reach 13 L/kg.⁸ blood concentrations of Cyclosporine are higher in leukocyte-rich and fat-rich organs. The non-cellular fraction of blood cyclosporine is carried mainly by lipoproteins with lesser binding to other plasma proteins (97%). Partitions of cyclosporine levels in red blood cells are two times more than plasma levels (2:1). Cyclosporine has the first-pass effect metabolized in the intestine and liver. It is widely distributed outside the vascular compartment. Its metabolism and elimination have first-order kinetics in patients.^7,10

Cyclosporine is primarily metabolized by the CYP3A4 member of the cytochrome P450 superfamily. CYP3A4 converts Cyclosporine into over 30 metabolites via hydroxylation, demethylation, sulfation, and cyclization at position one without ever disturbing the cyclic structure. It is primarily excreted in bile (90%) with less than 1% contribution of the parent drug. Urine excretion accounts for 6% of the total oral dose, Cyclosporine crosses the placenta and is excreted in human milk. All the metabolites have reduced biological activity and toxicity compared to the parent drugs in blood and urine. The elimination of Cyclosporine from the blood generally is biphasic with T1/2 of 5-28 h. The average half-life of Cyclosporine is approximately 19 hours.⁹

Cyclosporine levels are measured by High-performance liquid chromatography (HPLC) and radioimmunoassay. Cyclosporine concentrations of more than 400 ng/ml after 12 hours of prescription predispose a person to side effects (toxic concentration with HPLC). However, Cyclosporine poisoning is mainly diagnosed based on AUC and the toxic manifestations.¹⁰

Evidence from these early publications suggested that cyclosporine overdose is usually having minimum morbidity. However, renal failure, encephalopathy, and mortality and morbidity from cyclosporine overdose have been reported. The possibility of occurrence of cyclosporine toxicity should always be kept in mind in transplantation settings because Cyclosporine has a narrow therapeutic index, unpredictable pharmacokinetics, and a considerable probability of medication errors. The present study aims to characterize manifestations of acute cyclosporine overdose and determine serum concentrations that are predictive of poisoning severity and describe the effectiveness of therapeutic interventions used to manage cyclosporine overdose.¹¹

Methods

This systematic review investigated the literature reporting on cases of chronic Cyclosporine overdose in humans. The study protocol was constructed in advance and registered at https://www.crd.york.ac.uk/prospero with registration number CRD42020185634. The following definitions were used for this review. We defined “acute on chronic exposure” as an intentional or unintentional acute ingestion of Cyclosporine occurring within a 24-h period in a patient who had been exposed to Cyclosporine. We defined “chronic exposure” as exposure to Cyclosporine due to therapeutic use or ingestion of supratherapeutic doses for longer than 24 h. We defined an “adult” as a person over 18 and a “pediatric” as those below 18. Peak concentration is the highest concentration reported in a given case that may not represent the actual peak concentration (C-max). We defined a serum cyclosporine concentration of more than 400ng/ml or more as a supratherapeutic concentration.

Eligibility criteria

We included all cases of acute and acute chronic Cyclosporine exposed to both adult and pediatric patients. We excluded cases of chronic exposure and reports of adverse effects due to therapeutic use. On the other hand, we defined a 150 ng/ml--400 ng/mL serum concentration threshold for cyclosporine toxicity, 15mg/kg for oral, and 5--6 mg/kg for parenteral drug administration. We did not exclude cases based on serum concentrations as it was impossible to determine precisely when the blood samples were drawn (e.g., the serum concentration was at a therapeutic range because it was collected late in the course of the overdose). When a report did not meet the inclusion or exclusion criteria, data extractors took the following actions to reach a consensus. The final decision was left to the reviewer.

Outcome measures

The primary outcome measure was the clinical manifestations of acute or acute chronic cyclosporine overdose. Secondary outcomes included the relationship between the highest reported serum cyclosporine concentration for each case and poisoning severity and therapeutic overdose interventions and their effectiveness.

Search strategy

This systematic review investigated the literature reporting on acute and acute chronic cyclosporine overdose cases in humans. To find details of patients with CSA overdose in the literature, three accredited scientific databases, MEDLINE, Pub Med, and Science Direct, were explored statistical sources from January 1, 1983, to April 31, 2020.

Searching sources were ('cyclosporine'[Major]) plus [overdose /medication errors/poisoning/intoxication/toxicity / adverse effect]. Moreover, Conference proceedings and meeting abstracts of the EAPCCT (European Association of Poisons Centers and Clinical Toxicologists) and, NACCT (North American Congress of Clinical Trial) registries and Google Scholar were searched.

We identified 21900 journal article outputs after 1983 (the year Cyclosporine received approval from the US Food and Drug Administration for use in transplantation). After screening, most of these articles were irrelevant to this report. So, the Author chose only 81 cases based on their relevance to building this review on cyclosporine overdose. In addition, other useful articles were added to explain the reports further. (Fig. 1)

Fig. 1.

Flow diagram of the different phases of the literature review.

Statistical analysis

Data were analyzed using the statistical package for social sciences (SPSS) 17. Mann–Whitney U-test was performed to test the dose dependence of symptoms. Odds ratios were determined for the association between overdoses and subsequent active management steps undertaken.

Results

The literature search identified 21900 records. Duplicated records including 250 articles and minimal abstract 350 articles excluded. Many articles were excluded from our review based on chronic toxicity, adverse drug reaction, and irrelevant articles. We identified 81 cases of acute cyclosporine overdose with a documented serum concentration.

Forty-one (50%) patients were female, and 31(37%) were male. Gender was not specified in 13(13%) cases. The patients' ages ranged from 1 day to 71 years. Most patients had been prescribed Cyclosporine for the treatment of organ transplants (81%) and others (19%). Pediatric patients with cyclosporine overdose accounted for 29.2% of the treatment of the disease. Overdose occurred because of medication error or change from one form of Cyclosporine to the other. Patients' information is displayed in Tables 1, 2, and 3.

Table 1.

Cyclosporine only overdose.

Author	Age	Sex	Indication	Dosage, mg/kg	Concentration, Ng/ml	Sign and symptom	Treatment
Ceschi^11	51 y	Male	Lung transplant/ Acc	5.62 mg/kg IV	1256 ng/ml	Coma	ICU admission,
Ceschi^11	18 y	Female	Bone MT/ Acc	3.57 mg/kg IV	500 ng/ml	Two seizure Phenobarbital	Phenobarbital
Ceschi^11	4 m	Male	Heart T/ Acc	12 mg/kg PO	374 ng/ml	Asymptomatic	Dimethicone
Ceschi^11	30 y	Female	Renal T/ Acc	5.26 mg/kg	<400 ng/ml	Asymptomatic	Nasogastric tube aspiration
Ceschi^11	3 y	Male	Renal T/ Acc	20.83 mg/kg		Asymptomatic	No treatment
Ceschi^11	71 y	Male	Heart T/ Acc	7.2 mg/kg		Confusion and agitation	No treatment
Ceschi^11	4 y	Male	BMT/Acc	16.7 mg/kg	1500 ng/ml	Transient renal impairment	No treatment
Ceschi^11	2 m	Female	Hemophagocytic Lymphohistiocytosis/ Acc	315.8 mg/kg	836 ng/ml	HTN	Nasogastric tube aspiration
Ceschi^11	5 m	Male	Heart T/ Acc	50	750 ng/ml		Single-dose activated charcoal
Ceschi^11	20 y	Male	Suicidal intent 5*usual dose	76.92 mg/kg		Asymptomatic	No treatment
Ceschi, et al^11	55 y	Male	Lung T/Acc	12.27 mg/kg	1395	Asymptomatic	No treatment
Ceschi, et al^11	39 y	Female	Suicidal intent	4.35 mg/kg		Asymptomatic	No treatment
Arellano^12	35 y	Female	MR/ Acc	2500 mg	A/326 ng/ml	Asymptomatic	No treatment
Arellano^12	43 y	Male	MS/ Acc			Asymptomatic	No treatment
Arellano^12	48 y	Female	Thyroiditis/Acc	2500 mg/37.6 mg/kg		Dead	No treatment
Arellano^12	12 d	Male	Prematurity/Acc	100 mg IM/179 mg/kg	5388 ng/ml	Cyanosis, acidosis, hypotension, renal failure, hypotension, ARF	No treatment
Arellano et al^12	Neonate	Female	Thrombocytopenia/Acc	1200 mg IV	5388 ng/ml	Cyanosis, metacidosis, hypotention, anemia. ARF, Thrombocytopenia. Death	No treatment
Arellano et al^12	44 d	Female	Prematurity/neuroblastoma/Acc	50 mg IM/18.7ng/ml	520 ng/ml	Cyanosis, met acidosis, hypotension, anemia. ARF, Thrombocytopenia	No treatment
Arellano et al^12	Neonate		Prematurity/Acc	100 mg/IM/18.7 mg/kg	2040 ng/ml	Hyponatremia, oliguria, edema Hepatic toxicity, renal failure	No treatment
Arellano et al^12	8 d	Female	Prematurity/Acc	100 mgIM/42.9 mg/kg	2540 ng/ml	Oliguria, hyponatremia	No treatment
Arellano et al^12	10 d	Male	Prematurity/Acc	100 mgIM/49 mg/kg	2540 ng/ml	Oliguria, hyponatremia	No treatment
Arellano et al^12	11 y	Female	Acc	500 mg		Vomiting	No treatment
Arellano et al^12	Elderly	Male	Acc	5000 mg		Asymptomatic	No treatment
Arellano et al^12	4 y	Female	Acc	40 mg/kg		Asymptomatic	No treatment
Arellano et al^12	1 y	Male	Acc	20 mg/kg		Asymptomatic	No treatment

Cyclosporine only overdosage. LT. lung: transplant, RT: renal transplant, CT: cardiac transplant, LT: liver transplant, GVHD: graft versus host defense, MS: multiple sclerosis, BMT: bone marrow transplant, ALL: acute lymphocytic leukemia, AML: acute myelocytic leukemia.

Table 2.

Cyclosporine Mixed Overdosage.

Author	Age	Sex	Indication	Dosage, mg/kg	Concentration, Ng/ml	Sign and symptom	Treatment
Arellano^12	2 m		LT/Acc	500 mg-104 mg/kg	447 ng/ml	Vomiti ng	No treatment
Arellano^12	11 y	Female	BMT/Acc	5000 mg		Vomiti ng, mild drowsiness	No treatment
Arellano^12	2.5 y	Male	BMT/Acc	500 mg	2800 ng/ml		No treatment
Arellano^12	37 y	Female	RT/Acc	17000 mg		Tachycardia	Dead
Arellano^12	31 y	Male	RT	30 mg/kg iv	1200 ng/ml	Abdominal pain, hyperbilirubinemia	No treatment
Arellano^12	3 y	Male	LT/Acc	47 mg/kg		none	No treatment
Arellano^12	3 y	Male	RT/Acc	45 mg/k		none	No treatment
Arellano^12	32 y	Male	Renal transplant/Acc	60 mg/kg		none	No treatment
Arellano^12	48 y	Female	Renal transplant/Acc	62 mg/kg		Nausea	No treatment
Arellano^12	27 y	Male	Renal transplant/Acc	65 mg/kg/3500 mg		Headache, tachycardia	No treatment
Arellano^12	67 y	Male	Renal transplant/Acc	71 mg/kg/5000 mg		Nausea, vomiti ng, Headache	No treatment
Arellano^12	37 y	Female	Renal transplant/Acc	83 mg/kg/5000 mg		Headache	No treatment
Arellano^12	2 m	Male	Liver transplant/Acc	104 mg/kg/500 mg		Vomiti ng, mild	No treatment
Arellano^12	11 y	Female	BMT/Acc	149 mg/kg,5000 mg		drowsiness	No treatment
Ceschia^11	20 y	Female	ALL/Acc	76.92 mg/kg	>3000 ng/ml	conscious depression within 5h	Si ngle-dose activated charcoal 15 g
Ceschia^11	55 y	Male	Suicidal intent	29.41 mg/kg		HTN	Si ngle-dose activated 90 g
Ceschia^11	39 y	Female	CT/Acc	16 mg/kg		Asymptomatic up to 5 120 h	No treatment
Ceschia^11	52 y	Female	Scleroderma/Su	2.88 mg/kg		Vomiti ng	No treatment
Ceschia^11	24 y	Female	RT/Su	5.7 mg/kg		Vomiti ng and mild abdominal pain 3 h post overdose	No treatment
Ceschia^11	39 y	Female	CT/Su	4.48 mg/kg/A		Headache within 4 h of overdose	No treatment
Ceschia^11	75 y	Female	RT/Su	8.06 mg/kg/A		Asymptomatic	No treatment
Ceschia^11	19 y	Female	Systemic lupus/Su	48.4 mg/kg/A		Somnolence 2 h after overdose	NGT,Gastric washi ng
Perrot, et al	51 y	Male	LT/Acc	IV/A	>8200 ng/ml	Coma, sever Brain edema	Death
Wallemacq et al^13	23 y	Male	ALL/Acc	25000 mg		Anxiety, Diahrea, Vomiti ng, atrial fibrillation, Mild RF	No treatment
Baumhefner et al^14	43 y	Male	MS/Acc	25000 mg	1778 ng/ml	Paresthesia. dysesthesia, hyperesthesia, gum ulcer, flushi ng, abdominal pain, leg edema	No treatment
Anderson. et al^15	4.5 y	Female	Prune-belly syndrome/Acc	3000 mg	190 ng/mL		Charcoal administration
Diav-Citrin, et al^16	1 y	Male	Immunodeficiency/Acc	70 mg	5000 ng/ml	Irritability, face flushi ng, hypertension
Kakoda et al^17	31 y	Male	RT/Acc		4000 ng/ml	Abdominal pain, abdominal distension. liver enzyme rise,	Whole Blood Excha nge
Braakman et al^18	48 y	Female	GVHD/Acc		640 ng/ml	Stroke like symptom	No treatment
Velu, et al^19	19 y	Female	ALL/Acc		900 ng/ml	Headache, seizure, brain death	No treatment
Sherodure, et al^20	31 y	Female	RT/Acc	5000 mg	1550 ng/ml	Headache, Nausea, abdominal pain, Dizziness	No treatment
P. Shechter, et al^21	31 y	Female	ALL/Acc		6640 ng/ml	Renal failure, Death	Hemodialysis
Berden, et al^22	-		BMT/Acc		600 to 1000 ng/ml	Coma, quadriparesis,	No treatment
Berden, et al^22	-		BMT/Acc		600 to 1000 ng/ml	Coma, quadriparesis,	No treatment
Berden, et al^22	-		BMT/Acc		600 to 1000 ng/ml	Coma, quadriparesis,	No treatment
Berden, et al^22	-		BMT/Acc		600 to 1000 ng/ml	Coma, quadriparesis, paraparesis	No treatment
Berden, et al^22	-		BMT/Acc		600 to 1000 ng/ml	Coma, quadriparesis, ataxia, paraparesis	No treatment
Atkinson et al^23	37 y	Male	BMT/Acc		520 ng/ml	Tremore, leg weakness, behavioral abnormality, memory loss, Died	No treatment
Sa nghi et al^24	31 y	Male	Red cell Aplasia/Acc	12 mg/kg	1360 ng/ml	Atrial fibrillation, seizure	No treatment
Lovecchio^25	61 y	Male	RT/Acc	1000 mg	2438 ng/ml	fine tremor, fasciculation,	No treatment
Nghiem, et al^26	61 y	Male	RT/Acc	7500 mg	3687 ng/ml	Hepatic enzyme rise, mild brain, renal failure	No treatment
Leitner, et al^27	68 y	Male	RT/Acc		1100 ng/ml		Gastric lavage, cholestyramine, WBE
Shah et al^28	-	-	-		584 ng/ml	Headache, blurri ng of vision, seizure	No treatment
Shah et al^28	-	-	-		1075 ng/ml	Visual flashes, seizure.	No treatment
Shah et al^28	-	-	-		533 ng/ml	Seizure (Acute on chronic)	No treatment
Gaggero, et al^29	14 y	Female	ALL		1300 ng/ml	Epilepsy (Acute on chronic)	Phenobarbital
Gaggero, et al^29	8 y	Female	FA		768 ng/ml	Epilepsy (Acute on chronic)	Phenobarbital
Gaggero, et al^29	4 y	Male	Osteoporosis		2410 ng/ml	Epilepsy (Acute on chronic)	Phenobarbital
Gaggero, et al^29	15 y	Female	ALL		551 ng/ml	Epilepsy (Acute on chronic)	Phenobarbital
Gaggero, et al^29	9 y	Female	ALL		1824 ng/ml	Epilepsy (Acute on chronic)	Phenobarbital
Tafazoli^30	26 y	Female	ANL		1000 ng/ml	Nausea, vomiti ng, flushi ng, chest tightness, tremor, vertigo, Tachycardia	No treatment
Fahimi et al^31	54 y	Female	LT	1500 mg	400 ng/ml	Nausea, vomiti ng, weakness, tremor, hypertension, abdominal pain, HTN	TNG adminis
Moorma, et al^32	38 y	Female	GVHD	5000 mg	1797 ng/ml	seizure	a si ngle dose of activatedcharcoal 50 g, phenobarbital.WBE
Kwon, et al^33	55 y	Male	CT	5000 mg	8900 ng/ml	Seizure, coma	WBE
Zylber-Katz, et al^34	60 y	Male	RT	10000 mg/Suicide	1800 ng/ml	coma	Charcoal, flumazenilIv antibiotic
Dussol, et al^35	60 y		LT	30 mg/kg Per day	4100 ng/ml	Acute renal failure, hepatic enzyme rise, Icterus	Hemodialysis

LT. lu ng transplant, RT: renal transplant, CT: cardiac transplant, LT: liver transplant, GVHD: graft versus host defense, MS: multiple sclerosis, BMT: bone marrow transplant, ALL: acute lymphocytic leukemia, AML: acute myelocytic leukemia. FA, Fanconi's anemia

Table 3.

Demographic, Severity Toxicity, and Intervention Procedure Results.

Variables	Percentage
Female	48%
Male	35%
Unknown sex	18%
Death	5%
Severe Toxicity	51%
Minimal to Moderate Toxicity	49%
Gastric decontamination	6%
Charcoal administration	5%
Whole blood exchange	5%

Form of cyclosporine overdose

Cyclosporine poising is prevalent among transplantation patients. Oral overdose is common but parenteral overdose related to high fatality and morbidity needs more intervention. Almost unintentional overdose is caused by a medication error or changes from one form to another. Dosages are not equal (like Sandimmune to Neoral). Unintentional overdose occurred almost without signs and symptoms, discovered when cyclosporine level was measured. Thirteen patients had not been prescribed Cyclosporine and ingested it intentionally as part of a suicide attempt (16%).

Clinical features of cyclosporine overdose

Clinical manifestations of cyclosporine overdose, mostly gastrointestinal (GI) systems, cardiovascular systems, renal systems, and nervous systems, are summarized in Table 4.

Table 4.

Common Clinical manifestations.

Clinical manifestations
Altered consciousness(coma) GCS (Glasgow coma scale) < 8	8.6%
Seizure/Status epileptics	13.5%
Drowsiness	7.4%
Tachycardia	6%
Ataxia	2.5%
Atrial flutter	3.6%
Face flushing	1.2%
Nausea/Vomiting	13%
Hepatitis	4%
Headache	7.4%
Hypertension	4.9%
Tremor	1.2%
Transient kidney injury	14.8%
Abdominal distension	2%
Behavioral disorder	1.2%
Face flushing	1.2%
Paresis	7.5%
Leg edema	3.7%
Gum ulcer	1.2%
Death	7.4%
Asymptomatic	21%

We categorize signs and symptoms of cyclosporine overdose based on the severity of morbidity and mortality that occurred during an overdose. Mild to moderate Toxicity usually occurs via oral administration and may include headache, nausea, vomiting, hypertension, dysesthesias, abnormal taste, flushing face, postural tremor, fasciculation, and edemas. Severe Toxicity usually occurs via the parenteral administration and may include hyperkalemia (severe), nephrotoxicity, hepatotoxicity, encephalopathy, neurotoxicity, gastrointestinal bleeding, metabolic acidosis, allergic reaction, acute lung injury, CNS depression, seizure, coma, dysrhythmias, and cardiac arrest (Table 1).

GI manifestation

Nausea (6%)^34,35 and vomiting (13%)^{1,2,4,5,7,8,36} is a common manifestation and first sign of cyclosporine overdose. Abdominal distention is another symptom of GI involvement (2%).^2,7,9,37 Gum ulcers occurred in 2.5% of patients.³⁷ An increase of hepatic enzymes was seen in (4%) of patients.^2,7,9,37

Cardiovascular manifestations

Cardiovascular manifestations that are signs of cyclosporine toxicity include hypertension which affects 5% of patients,^1,5,10,38 hypotension (4% of patients),¹ cardiac tachyarrhythmia (6% of patients),^2,11–13 and AF arrhythmia (3.7% of all patients).^12,13

Renal manifestation

Acute renal failure transiently is caused by cyclosporine overdose. It affected 11% of patients.^2,4,13,14,38 Moreover, hyponatremia and leg edema associated with renal failure occurred in 3.7% of patients.^1,13,15,16

CNS manifestations

Toxic tremor's primary symptom in CNS caused by cyclosporine overdose occurred in our patients (2.4%).³⁶ Other symptoms like paresthesia (1.2%), Headache (7.4%),^34,39,40 Ataxia (1.2%), paresis (7.4%), stroke (1.2%), vertigo (2.5%), behavioral change (1.2%) [56], headache (7.5%)^34,39,40 drowsiness (7.4%)^{23–25,41,42} face flushing (1.2%).

The above symptoms were measured as mild to moderate CNS involvement in cyclosporine toxicity. The seizure occurred in 12% of patients.^1,13,17–19 Coma was highly related to death in our patients (13.5%)^1,5,13,17,18 because of severe cyclosporine toxicity (7.4%). Cyclosporine neurotoxicity may be related to hypomagnesemia and hypocholesteremia.^20–22

Cyclosporine-only overdose cases

Most patients have unintentional poisoning due to dose mis-administration or a change from one form to another (Sandimmune to Noral). Table 2 shows that two patients have intentionally overdosed.

Cyclosporine concentration and poisoning severity

In our reviews, serum cyclosporine overdose is not associated with the severity of cyclosporine poisoning. The most fatality occurred in cyclosporine concentrations above 3500 ng/ml and patients with severe neurologic symptoms except for one case.²³

Oral cyclosporine overdose may be mild or with no symptoms up to 150_400 mg/kg (10_25 times the therapeutic dosage).⁸ Almost parenteral overdose has severe symptoms and signs of poisoning.

Therapeutic interventions and their effectiveness

Gastrointestinal decontamination

Cyclosporine absorption is erratic and unpredictable, absorption of Cyclosporine is slow and peak concentrations in blood are observed one to eight hours after oral administration (average 2 to 5 hours). Data analysis (De Meer, et al) on overdose patients showed that the half-life of cyclosporine absorption occurs at 2.7 h during the use of the charcoal and 9.1 h afterward.⁴³ Our data suggest that charcoal administration may diminish the absorption of Cyclosporine, which could be effective 5 h or more after the overdose in some patients.⁴⁴

Cyclosporine absorption is highly dependent on Bile acid excretion. For this reason, theoretical multiple-dose charcoal may be prior to single-dose charcoal administration. Cyclosporine overdose patients used gastric lavage (n = 4, 5 %), charcoal single overdose (n = 4, 5%), and charcoal multiple doses (n = 1).^7,28,36

Basic treatment

Basic treatments include: Establishing a patent airway. Suction if necessary.

Watch for signs of respiratory insufficiency and assist with ventilation if needed.

Administer oxygen with a non-rebreathing mask at 10 to 15 L/min.

Monitor for pulmonary edema. Monitor for shock and treat if necessary.

If a seizure occurs, it should be controlled with anticonvulsant drugs. Orotracheal or nasotracheal Intubation for airway control in unconscious patients with severe pulmonary edema or respiratory arrest is used.

Apply positive pressure ventilation techniques with a bag valve mask or ventilator devices.

Monitor cardiac rhythm and treat arrhythmias if necessary. Use normal saline if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema. Administer fluid cautiously for hypotension with signs of hypovolemia.

Watch for signs of fluid overload.

Pharmacoenhancement therapy

Cyclosporine is extensively metabolized, and its concentration may be influenced by drugs that affect microsomal enzymes, particularly cytochrome P-450 IIIA. Substances that inhibit this enzyme decrease metabolism and increase cyclosporine levels, such as diltiazem, fluconazole, ketoconazole, and erythromycin administered in clinical practice to save the use of Cyclosporine. Drugs like phenytoin, phenobarbital, carbamazepine, octreotide, and ticlopidine are inducers of cytochrome P-450 activity that could increase cyclosporine metabolism activity and decrease cyclosporine concentrations.

Treat seizures caused by cyclosporine overdose with phenytoin and phenobarbital to get seizure treatment and enhancement of cyclosporine catabolism using the induction hepatic cytochrome CYP3A system. No clinical data evaluate the efficacy of this modality on cyclosporine overdose, two patients documented treatment with phenobarbital for seizure and cyclosporine enhancement therapy.⁴²

Extracorporeal elimination

When an overdose of Cyclosporine is observed, it is important to consider that hemodialysis and hemoperfusion are not responsive techniques. Cyclosporine would have limited clearance with a conventional hemodialyzer available in the 1970s and 1980s, with up to 1% cyclosporine removed by this dialyzer and the use of a modern high-efficiency dialyzer with greater middle molecule clearance.⁴⁴

It might provide some minimal adjunctive removal for any unbound drug component; the decision to combine HD with HP was made based on the presence of protein in Cyclosporine so that it cannot be removed effectively using hemodialysis alone (about less than 1 percent).⁴⁵ Also, efficient clearance of Cyclosporine by maximizing the extracorporeal blood flow during the treatment would have been predisposed to the rapid reduction of BUN concentration and subjected the person to dialysis disequilibrium. With combined HD/HP, the hemodialysis component permitted the simultaneous gradual and safe correction of the azotemia, electrolyte acid-base, and fluid consequences of the AKI concurrent with the adsorptive removal of fluid Cyclosporine.^33,46

Whole blood exchange

Cyclosporine has a large Vd of about 13 L/kg and a 90–98% capacity to bind plasma protein (mostly high-density lipoproteins). Plasma exchange cannot eliminate Cyclosporine from the patients.⁴⁷ In severe cyclosporine toxicity, we need rapid removal of Cyclosporine from deep-sited tissues. Whole blood Exchange was used in four cases; three patients had a full recovery and one patient died.^9,47–49

These cases showed severe cyclosporine poisoning and a high level of Cyclosporine might need whole blood exchange. (> 1500 ng/ml). The whole Blood Exchange procedure is a one-time erythrocyte aphaeresis or erythrocyte exchange, then multiple total plasma exchanges had to be done up to normalized cyclosporine level. This procedure seems to be effective in life-treating cyclosporine overdose but needs more cases for approval. Kwon et al., present a case with treatment only plasma apheresis leads to complete recovery.³³

Whole blood exchange modality causes more rapid and efficient cyclosporine level Reduction. (Fig. 2) (See Fig. 3).

Fig. 2.

The effects of different methods in the treatment of cyclosporine poisoning.

WBE: whole blood exchange.

Fig. 3.

Relation between degrees of poisoning with cyclosporine level.

Discussion

Cyclosporine poisoning often occurs in organ transplant patients, and fifty percent have severe organ systems toxicity. Cyclosporine overdose has a 5% mortality. Almost all patients who receive therapy on time after the clearance of cyclosporine toxicity have no sequel; more than 94% of patients have a complete recovery which is rarely associated with a permanent disability. There is no linear relationship between cyclosporine levels and the toxic effect of Cyclosporine. Multiple factors such as the type of organ transplant, background disease, duration of drug use, and forms of Cyclosporine be associated with the outcome.

Multiple analytic pharmacokinetics showed that AUC and C_2h instead of cyclosporine levels better predict cyclosporine toxicity.⁵⁰

Parenteral overdose is more dangerous than oral overdose; almost fatality is related to cyclosporine IV or IM overdose.

The possibility of occurrence of cyclosporine toxicity should always be kept in mind in transplantation settings because Cyclosporine has a narrow therapeutic index, unpredictable pharmacokinetics, and a considerable probability of medication errors. Oral cyclosporine overdose almost has no symptoms. In oral overdose, wrong dose selection, adjustment of cyclosporine dose, and change from one form to another haven't uniformed primary sources of oral cyclosporine overdose. An oral overdose (10-time to 25-time therapeutic dosage) has no symptoms or minimal signs (150_400mg/kg). No linear relationship between cyclosporine level and signs and symptoms of cyclosporine poisoning was observed, Fig. 3. Mortality is almost associated with severe neurologic signs and symptoms.

Pediatric patients are more prone to morbidity and mortality than adults because of the prematurity of the metabolic pathway.

Oral overdose of Cyclosporine has a benign feature with a good outcome.

Gastric decontamination usually may affect one hour after overdose, cyclosporine absorption from the gastrointestinal starts from 1.5--2 hours to 8 hours post-ingestion. GI decontamination after one hour may be reasonable and reduce the toxic effect of cyclosporine positioning.

Charcoal reduces AUC and peak cyclosporine level C-max. However, charcoal multiple dosages are theoretically better than charcoal mono doses. No data represent the priority of a single charcoal dose over multiple charcoal dosages. Evidence like the dependency of Sandimmune to bile acid secretion and multiple peaks after the GI absorption phase suggest charcoal multi-dosage over single charcoal. Extracorporeal removal has minimal effect on the elimination of Cyclosporine.

Data showed hemodialysis might reduce up to one percent of the whole Cyclosporine and affects cyclosporine elimination. However, for patients with background renal disease susceptible to renal toxicity, hemodialysis may reduce nephrotoxicity due to cyclosporine poisoning.

Pharmcoenhancment therapy may reduce cyclosporine levels, Cyclosporine metabolized with cytochrome CYP3A subfamily. Drugs including phenobarbital, phenytoin, and rifampin, induce this cytochrome and may reduce cyclosporine levels at poisoning time. Plasmapheresis theoretically has minimal effect on cyclosporine elimination, Cyclosporine is mainly absorbed into RBC and remains bound to lipoprotein 2:1.

Whole blood exchange in multiple cases with toxic kinetic analysis showed elimination of Cyclosporine better than plasmapheresis and had good outcomes so one of six cases had a fatality. Nevertheless, Whole Blood Exchange has many side effects, including hypocalcemia, allergic reaction, and thrombocytopenia.

Patients who have an oral overdose with no sign or minimal sign can be observed for 6 hours.

Patients with severe signs and those with parenteral overdose must be admitted to ICU. The recovery from severe signs and symptoms equals the disposition patient from ICU.

When an overdose occurs in patients prescribed cyclosporine therapy, the drug may be withheld for a few days, or alternate-day therapy may be initiated until these patients are stabilized or change to another drug like Tacrolimus, Sirolimus, or Azathioprine in transplantation patients to avoid the lack of immunosuppression in the transplant patient.

Conclusions

Cyclosporine overdose is mild poisoning. Standard procedures like GI decontamination, airway protection, charcoal administration, and support are used. Measures resolved overdose ultimately if it occurred on time.

Ethics approval

The study protocol was constructed in advance and registered in Prospero.

Availability of data and material

The data is all presented in the text.

Funding

None.

Authors' contributions

Data were extracted by Melika Ebrahimian MD and final review data by Sahel Shafiee MD.

Acknowledgments

We appreciate the Research Center, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences