CYCLOSPORINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Ciclosporin
2) CyA
3) Cyclosporin A
4) CAS 59865-13-3
5) 27-400

1.2.1) MOLECULAR FORMULA
1) C62H111N11O12

Available Forms Sources

1) CycloSPORINE is available as 25 and 100 mg soft gelatin capsules, 100 mg/mL oral solution (in a 50-mL bottle), and as a 5-mL ampule containing 50 mg/mL cycloSPORINE for IV infusion (Prod Info Sandimmune(R) oral capsules, oral solution, intravenous injection, 2012).
2) CycloSPORINE is also available as a 0.05% ophthalmic emulsion, packaged in single-use (0.4 mL) vials (Prod Info RESTASIS(R) ophthalmic emulsion, 2010).

1) CycloSPORINE is a cyclic polypeptide, composed of 11 amino acids, extracted from various fungus species (Eide & Belenker, 1992).

1) CycloSPORINE is primarily used as an immunosuppressant in organ transplantation to prevent organ rejection. It is also used to treat psoriasis, rheumatoid arthritis, other autoimmune disorders, and dry eyes (Prod Info Sandimmune(R) oral capsules, oral solution, intravenous injection, 2012; Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012; Prod Info RESTASIS(R) ophthalmic emulsion, 2010; Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: CycloSPORINE is a cyclic polypeptide extracted from fungal species. It is primarily used as an immunosuppressant for organ transplant, but is also used to treat psoriasis, rheumatoid arthritis, other autoimmune disorders, and dry eyes.
B) PHARMACOLOGY: The exact mechanism of action is unknown, but cycloSPORINE is thought to suppress helper T-lymphocyte proliferation, and activation. It is also thought to decrease lymphokine release.
C) TOXICOLOGY: CycloSPORINE inhibits sodium-dependent uptake of bile salt transport across canalicular membranes resulting in cholestasis. It is also directly nephrotoxic. Because it is an immunosuppressant, it can also increase risk of infection, lymphoma, and lymphoproliferative disorders.
D) EPIDEMIOLOGY: CycloSPORINE ingestion is an uncommon cause of poisoning. Ingestions are usually unintentional, and rarely result in severe manifestations. Parenteral overdose, though uncommon, are usually more serious than oral overdose.
E) WITH THERAPEUTIC USE

1) Hypertension, elevated BUN/serum creatinine, hirsutism, infection, tremor, gingival hyperplasia, headache, hypertriglyceridemia, nausea, vomiting, diarrhea, leg cramps, paresthesias, dizziness, stomatitis, edema, rash, arthralgia, flushing, leukopenia, thrombocytopenia, hemolytic anemia, depression, optic disc edema, intracranial hypertension, glomerular capillary thrombosis, pancreatitis, malignancy, diabetes, hyperuricemia, hyperkalemia, and hypomagnesemia have been reported with therapeutic use.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Usually occurs via the oral route of administration, and may include headache, nausea, vomiting, hypertension, dysesthesias, taste abnormalities, flushing, tremor, fasciculations, and edema.
2) SEVERE TOXICITY: Usually occurs via the parenteral route of administration, and may include hyperkalemia (severe), nephrotoxicity, hepatotoxicity, encephalopathy, neurotoxicity, gastrointestinal bleed, metabolic acidosis, allergic reaction, acute lung injury, CNS depression, seizure, coma, dysrhythmias, and cardiac arrest.

0.2.20)

A) CycloSPORINE is classified as FDA pregnancy category C. Based on the teratogenic and embryo-fetal toxicity observed in animals that received very high doses, cycloSPORINE may cause fetal harm when administered to pregnant women although it has not been shown to be a human teratogen with therapeutic use. CycloSPORINE has been shown to cross the placenta, and is excreted in breast milk.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Most exposures are mild and require only supportive care. Replete magnesium if needed.

B) MANAGEMENT OF SEVERE TOXICITY

1) Support respiratory and cardiovascular function as needed. Treat severe hyperkalemia, resulting in ECG changes, with dextrose/insulin and calcium. Treat seizures with benzodiazepines. Toxic nephropathy has been treated with low dose dopamine.

C) DECONTAMINATION

1) PREHOSPITAL: Generally, no decontamination is needed in the prehospital setting.
2) HOSPITAL: Activated charcoal may be utilized for worrisome ingestions.

D) AIRWAY MANAGEMENT

1) Provide supportive care.

E) ANTIDOTE

1) None

F) ENHANCED ELIMINATION

1) Because of its large molecular weight, hemodialysis or other forms of enhanced elimination are of no benefit.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with unintentional ingestions may be observed at home if asymptomatic.
2) OBSERVATION CRITERIA: Symptomatic patients and those with deliberate ingestions should be evaluated in a healthcare facility. Patients who have minimal symptoms 6 hours after ingestion may be discharged.
3) ADMISSION CRITERIA: Symptomatic patients requiring ongoing supportive care may need admission. Once asymptomatic for 6 hours, they may be discharged.
4) CONSULT CRITERIA: Severe poisoning may occur with large oral or parenteral exposures of cycloSPORINE. If concerned, consult a medical toxicologist for guidance. Consult specialists if hepatotoxicity, renal toxicity, or neurologic symptoms persist.

H) PITFALLS

1) Failure to rule out infection in overdose if patients have altered mental status as cycloSPORINE is an immunosuppressant. CycloSPORINE plasma concentrations should be checked as well. Overdose patients generally do well with supportive care. Be cognizant of co-ingestants.

I) PHARMACOKINETICS

1) Protein binding is 90%; volume of distribution is 3 to 5 L/kg. Under goes extensive hepatic metabolism via cytochrome P-450 3A enzymes. The mean elimination half-life ranges from 8.4 to 19 hours. Therapeutic trough plasma concentrations are 50 to 300 ng/mL.

J) TOXICOKINETICS

1) Trough plasma concentrations greater than 250 ng/mL have been associated with nephrotoxicity, and concentrations greater than 1000 ng/mL have been associated with hepatotoxicity.

K) DIFFERENTIAL DIAGNOSIS

1) Sepsis, encephalitis, meningitis, renal failure, encephalopathy, and other hepatotoxic or renal toxic agents.

0.4.4)

A) CycloSPORINE also comes as an ophthalmic solution used to treat dry eyes and may increase the risk of an ocular infection. Flush the eye copiously with tepid tap water or saline with at least 1 liter per eye. Consider using local anesthetic drops for pain control and to ease irrigation.

0.4.6)

A) Parenteral exposures are often more serious than oral ingestions. Treat in a similar manner to a large oral overdose.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) DIAPHORESIS was noted after accidental rapid IV injection of 250 mg (Wallemacq & Lesne, 1985).

3.3.4)

A) WITH POISONING/EXPOSURE

1) CASE REPORTS: A mild increase in blood pressure (from 110/65 to 160/100 mmHg) was noted after a massive oral overdose in an adult (Baumhefner et al, 1987). Mild transient hypertension (109/77) was also reported in a 2-month-old child given 500 mg orally (de Meer et al, 1989).

Heent

3.4.2)

A) WITH POISONING/EXPOSURE

1) FACIAL FLUSHING was noted in one case of overdose (Baumhefner et al, 1987).

3.4.3)

A) WITH THERAPEUTIC USE

1) CASE SERIES: CORTICAL BLINDNESS was described in 3 patients receiving cycloSPORINE following liver transplant. All 3 patients had an extremely low serum cholesterol level (De Groen et al, 1987).
2) CASE REPORT: Reversible cortical blindness was reported in an adult 19+ days post allogenic peripheral blood stem cell transplantation (Madan & Schey, 1997). Symptoms progressed to complete blindness over a 3 hour period along with generalized seizures. After 48 hours, complete resolution of cortical blindness was reported.
3) Sudden blindness has also been noted after bone marrow transplant (Rubin & Kang, 1987; Lopez Messa et al, 1986).
4) CASE REPORT: Onset of cortical blindness occurred on day 5 of cyclosporin A (trough levels did not exceed 240 ng/mL) in a 55-year-old woman liver transplant patient. Progressive generalized neurologic dysfunction subsequently developed. CycloSPORINE A was discontinued and neurologic status steadily improved over the following 10 days. When cycloSPORINE was restarted after a second liver transplant, episodes of altered sensorium recurred (Wilson et al, 1988).
5) CASE REPORT: Transient cortical blindness secondary to partial occipital seizures was described in a 5-year-old girl on therapeutic doses of cycloSPORINE following bone marrow transplantation. Her serum cycloSPORINE level on admission was 1,704 ng/mL. Symptoms resolved over the next 3 days after discontinuation of the drug. She was discharged with a cycloSPORINE level of 62 ng/mL, having suffered no serious sequelae. The mechanism proposed by the author is direct competition for hepatic metabolism by other drugs; the patient was also taking ketoconazole (Rubin, 1989).

3.4.6)

A) WITH THERAPEUTIC USE

1) GINGIVAL HYPERPLASIA

a) Gingival hyperplasia was reported in 4% to 16% of patients treated with cycloSPORINE (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012). In some reports, gingival hyperplasia occurred in up to 70% of patients (McGaw & Porter, 1988). Gingival hyperplasia usually occurs in susceptible patients within 3 months of starting therapy (Seymour & Jacobs, 1992). In 1 study, patients with gingival overgrowth had significantly higher salivary levels of cycloSPORINE than patients who did not (McGaw et al, 1987). Other risk factors for the development of cycloSPORINE-induced gingival hyperplasia include young age and high dose. Although it is not known why, the incidence of gingival hyperplasia is low in bone marrow transplant patients.
b) CASE SERIES: Mild reversible gingival hyperplasia is a common side effect of cycloSPORINE therapy. Of 100 patients treated, 53 had mild-moderate and 17 had marked severe hyperplasia. Hyperplasia was more common in children and adolescents (Daley et al, 1986).

B) WITH POISONING/EXPOSURE

1) CASE REPORT: Altered taste, a burning sensation in the mouth, and sore gums were reported in a multiple sclerosis patient who took 25 g over 8 days (Baumhefner et al, 1987).

Cardiovascular

3.5.2)

A) HYPERTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) INCIDENCE: CycloSPORINE therapy results in systemic vasoconstriction with an increase in both severity and incidence of hypertension (Textor et al, 1994). Combination drug therapy (cycloSPORINE and corticosteroids) following transplantation has resulted in up to 90% of patients developing clinical hypertension.
b) Hypertension may occur in approximately 50% of renal transplant patients and most cardiac transplant patients (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Mild hypertension (increase from 110/65 to 160/100 mmHg) was reported in a 43-year-old man who took 25 g over 8 days (Baumhefner et al, 1987).

B) ATRIAL FIBRILLATION

1) WITH POISONING/EXPOSURE

a) CASE REPORTS

1) Atrial fibrillation was described in a 23-year-old woman who accidentally received a 250 mg IV bolus injection (Wallemacq & Lesne, 1985).
2) A 61-year-old anephric patient scheduled for renal transplant received an inadvertent 1000 mg oral cycloSPORINE (microemulsion suspension) dose (LoVeechio & Curry, 1998). Symptoms of tremor, flushing, and an irregular heart beat occurred 1 hour after exposure. Atrial fibrillation and right bundle branch block were observed, but the patient's baseline rhythm returned within one hour with no intervention.
3) A 24-year-old man developed a tonic-clonic seizure and shortly afterwards was found to be in atrial fibrillation after receiving intravenous cycloSPORINE. Blood cycloSPORINE concentration shortly before the seizures was 1360 ng/mL (over 4 times the therapeutic concentration). He converted to sinus rhythm about 5 hours after the seizure (Sanghi & Ahmad, 2004).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH THERAPEUTIC USE

a) CASE SERIES

1) ADULT respiratory distress syndrome (ARDS) has been described in 2 liver transplant patients receiving cycloSPORINE through a central venous catheter (Powell-Jackson et al, 1984).

b) CASE REPORTS

1) Carbone et al (1987) described the occurrence of ARDS following oral cycloSPORINE therapy in a renal transplant asthmatic patient (Carbone et al, 1987). Five days after initiation of 850 mg/day, the patient developed respiratory distress with no evidence of infection, embolism, allergy, or urticaria.

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A feeling of "drunkenness" was described by a 31-year-old renal transplant patient who ingested 5 g (Schroeder et al, 1986).

B) HEADACHE

1) WITH THERAPEUTIC USE

a) In a clinical study of kidney patients randomized to receive cycloSPORINE (n=227), or azathioprine (n=228), 2% of cycloSPORINE-treated patients experienced headache compared with less than 1% of azathioprine-treated patients. In clinical trials of 892 patients, undergoing kidney transplant (n=705), heart transplant (n=112), or liver transplant (n=75), headache had a reported incidence rate of 2% (kidney transplant), 15% (heart transplant), and 4% (liver transplant) (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

2) WITH POISONING/EXPOSURE

a) Severe headache was reported shortly after ingesting 5 g (Schroeder et al, 1986).

C) HYPERESTHESIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Hyperesthesia in the hands and a burning sensation in the feet were described following ingestion of 25 g over 8 days by a patient with multiple sclerosis. Dysesthesias resolved a week after discontinuation of cycloSPORINE (Baumhefner et al, 1987).

D) SEIZURE

1) WITH THERAPEUTIC USE

a) CHRONIC TOXICITY

1) GENERALIZED SEIZURES have been described during therapeutic administration of cycloSPORINE to renal transplant patients (Nordal et al, 1985) (Shar et al, 1984) (Allen et al, 1985), and in bone marrow transplant patients (Velu et al, 1985; Atkinson et al, 1984; Barrett et al, 1982; Durrant et al, 1982) (Boogaerts et al, 1972) (Thompson et al, 1984), and following allogenic peripheral stem cell transplantation in one patient (Madan & Schey, 1997).
2) RISK FACTORS: Predisposing factors have included genetic predisposition, hypomagnesemia (Thompson et al, 1984) (Borland et al, 1985), concurrent neurotoxic drug therapy, aluminum overload (Nordal et al, 1985), and concomitant high-dose methylprednisolone therapy (Durrant et al, 1982) (Boogaert et al, 1982).
3) CASE REPORTS

a) A 13-year-old boy with a history of severe Crohn's disease was started on cycloSPORINE A for continued episodes of diarrhea and rectal bleeding despite high-dose corticosteroid therapy. Six days after the start of therapy the patient had multiple episodes of generalized tonic-clonic seizures and an MRI indicated findings that were typical of cycloSPORINE A central nervous system neurotoxicity. No clinical risk factors were reported (Rosencrantz et al, 2001).
b) PARTIAL OCCIPITAL SEIZURES were reported in a 5-year-old girl receiving therapeutic doses of cycloSPORINE after bone marrow transplantation. Blurred vision, headache, visual hallucinations, and transient cortical blindness were also observed. Serum cycloSPORINE concentration was 1,704 ng/mL. Symptoms rapidly resolved after discontinuation of the drug, and the patient was discharged after 3 days with a cycloSPORINE level of 62 ng/mL (Rubin, 1989).
c) A 24-year-old man developed a tonic-clonic seizure and shortly afterwards was found to be in atrial fibrillation after receiving intravenous cycloSPORINE. Blood cycloSPORINE concentration shortly before the seizures was 1360 ng/mL (over 4 times the therapeutic concentration(Sanghi & Ahmad, 2004).

E) TREMOR

1) WITH THERAPEUTIC USE

a) Tremors occurred during therapeutic use in 21% to 55% of patients (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).
b) CASE REPORT: A 61-year-old anephric man developed tremors and fasciculations after receiving 1000 mg of cycloSPORINE orally. Symptoms resolved within 24 hours (LoVeechio & Curry, 1998).

F) HEMIPLEGIA

1) WITH THERAPEUTIC USE

a) CASE REPORTS

1) Hemiplegia and focal seizures were reported in a 6-year-old boy receiving cycloSPORINE 3.5 mg/kg/day IV following allogeneic bone marrow transplantation. Plasma cycloSPORINE level was reported as 145 ng/mL. Cessation of the drug was followed by complete recovery within 6 hours. Serum magnesium level was normal; cycloSPORINE metabolite levels were not reported (Vellodi et al, 1987).
2) Flaccid hemiparesis was also seen in a 30-year-old woman taking 300 to 600 mg daily (Palmer & Toto, 1991).

G) COMA

1) WITH THERAPEUTIC USE

a) CASE REPORTS

1) Coma was reported in a renal transplant patient following 15.5 mg/kg/day for 20 days. Although cycloSPORINE was discontinued, the patient remained in a coma for 44 days, after which full recovery occurred (Berden et al, 1985).
2) A 64-year-old renal transplant patient developed somnolence and fever which progressed to coma 66 days after transplantation. Withdrawal of cycloSPORINE resulted in a fall in temperature and a normal EEG. Rechallenge on 2 subsequent occasions resulted in somnolence and abnormal EEGs (Wilczek et al, 1985).

H) HALLUCINATIONS

1) WITH THERAPEUTIC USE

a) CASE SERIES: Visual hallucinations were associated with elevated cycloSPORINE blood levels (747 ng/mL and 1212 ng/mL done by RIA, respectively) in 2 organ transplant patients (Katirji, 1987).

I) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) CASE SERIES: Evidence of diffuse white matter hypodensity on CT scan, accompanied by symptoms of cortical blindness, aphasia, disorientation, delusions, quadriplegia, hyperreflexia, coma, hyperventilation, and seizures, were described in 3 patients receiving cycloSPORINE following liver transplantation. All 3 had low serum cholesterol levels, which may have enhanced penetration of cycloSPORINE into the CNS. Further investigation disclosed 13 cases of cycloSPORINE-induced CNS symptoms with a mean serum cholesterol of 94 mg/dL, compared to 132 mg/dL in 35 asymptomatic patients (De Groen et al, 1987).
b) CHRONIC THERAPY: A 54-year-old man received an HLA-matched-unrelated bone marrow transplant for CML. The patient developed progressive encephalopathy and on day 79 he had a generalized seizure. Death occurred within 72 hours of stopping cycloSPORINE, due to central respiratory failure. Postmortem findings indicated diffuse patchy white matter edema and astrocytic injury without evidence of axonopathy, demyelination, microvascular injury, or infectious inflammatory process (Gopal et al, 1999).
c) CASE REPORT: A 76-year-old woman with a history of aplastic anemia and thrombocytopenia developed encephalopathy and elevated liver enzyme levels 13 days after starting cycloSPORINE therapy and taking diltiazem concomitantly (Jiang et al, 1999). The patient's neurological status rapidly deteriorated and she did not regain consciousness until 36 hours after drug cessation. Liver enzymes also improved.

J) CENTRAL NERVOUS SYSTEM FINDING

1) WITH THERAPEUTIC USE

a) The neurotoxic effects of high cycloSPORINE levels have been well documented (Bertoli et al, 1988; Deierhoi et al, 1988; Rubin, 1989).
b) There have been several reports of severe neurotoxicity in which cycloSPORINE concentrations were in the therapeutic range. In these cases, levels of the M17 metabolite of cycloSPORINE were significantly elevated. This metabolite may, therefore; be at least partially responsible for the neurotoxic properties of cycloSPORINE (Kunzendorf et al, 1988; Kunzendorf et al, 1989; Trull et al, 1989).
c) The incidence of cycloSPORINE-induced CNS toxicity appears to be inversely related to serum cholesterol concentration.

1) DeGroen et al (1987) showed a significantly greater incidence of neurotoxicity in patients whose total serum cholesterol was low as compared to those who did not experience such toxicity (De Groen et al, 1987).
2) It is theorized that if total serum cholesterol levels are low, the free or unbound fraction may rise, causing CNS toxicity (De Groen et al, 1987; Bhatt et al, 1988).

K) CEREBRAL EDEMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 51-year-old nonsmoker underwent bilateral sequential lung transplantation for pulmonary fibrosis and inadvertently received an infusion of cyclosporin at a rate of 30 mg/hr (instead of 3 mg/kg) for 13 hours immediately post-op. Within 3 hours of stopping the infusion the patient developed bilateral mydriasis and massive intracranial hypertension (up to 100 mmHg) along with increasing neurological impairment. The patient died 5 hours later from brainstem compression. Postmortem findings showed diffuse cerebral edema with herniation of the cerebellar tonsils (De Perrot et al, 2000).

L) SUBARACHNOID HEMORRHAGE

1) WITH THERAPEUTIC USE

a) Subarachnoid hemorrhage in the occipital region (confirmed by CT) has been associated with cycloSPORINE A (CSA) neurotoxicity following bone marrow transplantation. MRI showed cortical and subcortical edema in the posterior, temporal, occipital, and posterior frontal lobes bilaterally. Following cessation of therapy, cortical and subcortical edema resolved on follow-up MRI (Teksam et al, 2001).

M) PARESTHESIA

1) WITH THERAPEUTIC USE

a) In a clinical study of kidney patients randomized to received cycloSPORINE (n=227), or azathioprine (n=228), 3% of cycloSPORINE-treated patients experienced paresthesia compared with 0% of azathioprine-treated patients. In clinical trials of 892 patients undergoing kidney transplant (n=705), heart transplant (n=112), or liver transplant (n=75), paresthesia was reported at an incidence of 1% in kidney transplant, 2% in heart transplant, and in 1% of liver transplant patients (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

N) BENIGN INTRACRANIAL HYPERTENSION

1) WITH THERAPEUTIC USE

a) Benign intracranial hypertension (or elevated intracranial pressure) secondary to cycloSPORINE treatment in the setting of bone marrow transplantation may occur (Vincent et al, 2001; Saito et al, 1999; Cruz et al, 1996). One 11-year-old boy had been on cycloSPORINE to control graft-versus-host disease complicating allogeneic bone marrow transplantation 3 years earlier. He presented with a 1-month history of horizontal diplopia, with esotropia and bilateral optic disk edema. No intracranial lesion could be appreciated by MRI. The opening pressure of the lumbar puncture was 500 mm of water. Pseudotumor cerebri secondary to cycloSPORINE was diagnosed. Resolution of both esotropia and diplopia occurred within 5 days of discontinuing cycloSPORINE, while optic disk edema resolved within 3 months (Cruz et al, 1996).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) In a clinical study of kidney patients randomized to receive cycloSPORINE (n=227) or azathioprine (n=228), 2% of cycloSPORINE-treated patients experienced nausea/vomiting compared with less than 1% of azathioprine-treated patients. In clinical trials of 892 patients undergoing kidney (n=705), heart (n=112), or liver transplant (n=75), nausea/vomiting was reported in 4% of kidney transplant, 10% of heart transplant, and 4% of liver transplant patients (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

2) WITH POISONING/EXPOSURE

a) Intractable nausea, anorexia, and abdominal swelling have been described after overdose (Schroeder et al, 1986; Baumhefner et al, 1987).

B) DIARRHEA

1) WITH THERAPEUTIC USE

a) In a clinical study of kidney patients randomized to receive cycloSPORINE (n=227) or azathioprine (n=228), 3% of cycloSPORINE-treated patients experienced diarrhea compared with less than 1% of azathioprine-treated patients. In clinical trials of 892 patients undergoing kidney (n=705), heart (n=112), or liver transplant (n=75), diarrhea was reported in 3% of kidney transplant, 4% of heart transplant, and 8% of liver transplant patients (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

C) BILIARY CALCULUS

1) WITH THERAPEUTIC USE

a) CHRONIC TOXICITY

1) INCIDENCE/CASE SERIES: Pediatric heart or heart-lung transplant patients (n=90) receiving cycloSPORINE had a 6.7% rate of cholelithiasis compared with 1% of children (under 16 years) in the general population (Weinstein et al, 1995). Determining an exact cause is limited due to lack of a similar cohort population not receiving cycloSPORINE.
2) ADULTS: In several studies, adult transplant (kidney and heart) patients also had an increased incidence of cholelithiasis when given cycloSPORINE (reviewed in Weinstock et al, 1995).

D) PANCREATITIS

1) WITH THERAPEUTIC USE

a) In clinical studies, pancreatitis was reported rarely in kidney, heart, and liver transplant patients receiving cycloSPORINE (n=892) (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

E) STOMATITIS

1) WITH THERAPEUTIC USE

a) In clinical studies, mouth sores were reported rarely in all kidney, heart, and liver transplant patients who received cycloSPORINE (n=892) (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

Hepatic

3.9.2)

A) HYPERBILIRUBINEMIA

1) WITH THERAPEUTIC USE

a) Hepatotoxicity occurs in 4% to 7% of patients receiving high therapeutic doses and usually noted during the first month of therapy with elevations of hepatic enzymes and bilirubin, which decrease with a decrease in dose (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

Genitourinary

3.10.2)

A) TOXIC NEPHROPATHY

1) WITH THERAPEUTIC USE

a) In a study of pediatric heart transplant recipients, early exposure to cycloSPORINE A can result in renal dysfunction, which can persist even when the dose of cycloSPORINE is subsequently reduced (Hornung et al, 2001).
b) Nephrotoxicity occurs in 20% to 41% of transplant patients receiving cycloSPORINE. Nephrotoxicity is most likely to occur in patients with trough plasma (RIA) concentrations of greater than 500 ng/mL (Howes et al, 1983). However, some studies involving renal transplant patients have shown that 96% of patients with cycloSPORINE-nephropathy have trough plasma levels greater than or equal to 250 ng/mL (Gordon et al, 1985).
c) Moyer et al (1988) reported that renal toxicity was minimized to statistical nonsignificance (p less than 0.01) by using cycloSPORINE dosages that provided trough whole blood concentrations of 150 to 250 ng/mL (measured by HPLC) for the first four months of therapy, and 80 to 200 ng/mL thereafter (Moyer et al, 1988).

2) WITH POISONING/EXPOSURE

a) Mild evidence of renal dysfunction (slightly increased serum creatinine and BUN) have been described after accidental overdose in 2 renal transplant patients; however one patient was experiencing acute allograft rejection and continued to have worsening renal function (Schroeder et al, 1986), and the other patient was recovering from a graft rejection (Honcharik & Anthone, 1985a).
b) In a multiple sclerosis patient with normal baseline renal function, no evidence of renal impairment occurred after an overdose of 25 g over 8 days (Baumhefner et al, 1987). Evidence of mild renal insufficiency was noted after accidental bolus injection of 250 mg to a young patient with normal baseline renal function (Wallemacq & Lesne, 1985).

B) HYPERURICEMIA

1) WITH THERAPEUTIC USE

a) Hyperuricemia has occasionally been associated with cycloSPORINE treatment (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012). CycloSPORINE may cause hyperuricemia by interfering with the tubular excretion of uric acid. Elevated uric acid levels may result in gout. In comparative studies of renal transplant patients, cycloSPORINE has caused increased uric acid levels in 84% of patients and gout in 24% of patients. Risk factors for cycloSPORINE-induced gout include impaired renal function, concomitant diuretics, and being male (Lin et al, 1989; Noordzij et al, 1991).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Severe metabolic acidosis has been reported after parenteral overdose (Arellano et al, 1991).

Hematologic

3.13.2)

A) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) In randomized clinical studies of patients undergoing kidney transplants, leukopenia has been reported in 2% of cycloSPORINE recipients (n=227) compared with 19% of patients receiving azathioprine (n=228). Leukopenia has been reported in 6% or less of kidney, heart, and liver transplant patients receiving cycloSPORINE (n=892) (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

B) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) In clinical studies, thrombocytopenia has been reported in 2% or less of kidney, heart, and liver transplant patients receiving cycloSPORINE (n=892) (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

C) CAPILLARY THROMBOSIS

1) WITH THERAPEUTIC USE

a) Glomerular capillary thrombosis has occurred with cycloSPORINE therapy post-transplantation, with pathologic changes that included thrombosis of the renal microvasculature, hemolytic anemia, thrombocytopenia, and decreased renal function. Progression to graft failure may occur (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

Dermatologic

3.14.2)

A) EXCESSIVE HAIR GROWTH

1) WITH THERAPEUTIC USE

a) CASE SERIES: Hirsutism has been reported in 21% to 45% of renal, liver, or heart allograft recipients (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).

Musculoskeletal

3.15.2)

A) DRUG-INDUCED MYOPATHY

1) WITH THERAPEUTIC USE

a) CASE REPORTS: Myopathy was reported in 3 patients taking cycloSPORINE. These patients were also taking steroids, enalapril, and azathioprine. Causality is still somewhat in question (Chassagne et al, 1989; Goy et al, 1989; Grezard et al, 1990; Papa et al, 1985).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH THERAPEUTIC USE

a) In clinical studies, hyperglycemia was reported in 2% or less of kidney, heart, and liver transplant patients who received cycloSPORINE (n=892) (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2012).
b) Of the patients developing diabetes, approximately half will require treatment with insulin while others will require oral hypoglycemic agents or a special diet. In addition to diabetes, cycloSPORINE deposits in the pancreas have been observed (Mejia et al, 1989; Sumrani et al, 1991) Diabetes induced by cycloSPORINE occurs more frequently in patients with a family history of diabetes, patients older than 45 years, and patients heavier than 70 kg. Blacks and Hispanics are also at a higher risk. Other factors that are controversial in contributing to cycloSPORINE-induced diabetes include gender (male predominance), dose of cycloSPORINE, and having HLA-A or HLA-Bw haplotype (Sumrani et al, 1991; Boudreaux et al, 1987).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) INFUSION: Anaphylactoid reactions have occurred after intravenous cycloSPORINE therapy and appear to be related to the polyoxyethylated castor oil (Cremophor(R) EL) vehicle, which is not present in the oral preparation (Chapuis, 1985; Kahan et al, 1984; Leunissen et al, 1984; Freidman, 1985; Howrie, 1985).
b) Reactions usually occur during the second exposure or during long term infusion, but have been reported after the first dose of cycloSPORINE (Friedman et al, 1985; Magalini et al, 1986).
c) ORAL THERAPY: Anaphylaxis (severe hypotension {BP less than 60 mm Hg} and bradycardia {HR of 50 beats/min}) was reported in a 73-year-old woman with metastatic breast cancer within 30 minutes of ingesting cycloSPORINE capsules (total dose 1100 mg); 10 minutes later the patient collapsed. The patient recovered following supportive care (Kuiper et al, 2000).

B) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) CASE REPORTS

1) ORAL THERAPY: van Hooff et al (1987) reported a case in which a patient was hypersensitive to both the commercial, intravenous, and oral preparations (van Hooff et al, 1987). Eight hours after a single oral 400 mg dose, the patient experienced headache, erythema of the head, conjunctival edema, hypertension, and tachycardia.

a) Two months later, intradermal skin testing was negative for saline and for pure cycloSPORINE, but was strongly positive for histamine and for the solvent in the oral solution (polyoxyl-5-oleate, olive oil, and ethanol).
b) Subsequently he received 900 mg of the IV solution orally. After one hour, a generalized erythema of the skin developed and persisted for 24 hours, requiring antihistamine treatment. He was then challenged with a preparation of cycloSPORINE in maize oil, which he was able to take with no problems.

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL ANOMALY

1) CASE SERIES: In a study of 48 pregnant women being treated with therapeutic doses of cycloSPORINE, no evidence of direct hazard to the fetus was demonstrated. Of 43 live births, 34 were born healthy, 7 had physiological abnormalities, and 2 were born with birth defects. The malformations reported were probably not related to cycloSPORINE because the 38 babies who were exposed to the drug throughout pregnancy did not show any birth defects, and the malformations that occurred in the others did not show a common pattern (Cockburn et al, 1989).
2) Reviews of case series of pregnancies in women receiving cycloSPORINE after liver transplantation found no increased risk of congenital malformations or maternal complications (Rayes et al, 1998; Wu et al, 1998). Development did not appear to be adversely affected in the offspring (children up to 8 years old), although longer-term consequences are not known.
3) A case of hypoplasia of the right leg was reported in a neonate after maternal use of cycloSPORINE for kidney transplant. In addition to osseous malformation, this neonate experienced hypocalcemia, requiring intravenous calcium gluconate, on days 8 and 14 of life (Pujals et al, 1989).
4) According to the manufacturer, the outcomes of 116 pregnancies in women receiving cycloSPORINE , most throughout the entire gestational period of pregnancy, 90% of whom were transplant patients, have been reported. Low birth weight for gestational age and premature birth (gestational period less than 36 weeks) were the only consistent patterns reported. It is not possible to distinguish the effects of cycloSPORINE on these pregnancies from the effects of the other immunosuppressants, the underlying maternal disorders, or other aspects of the transplantation environment. Small size for gestational age was reported for 28% of the pregnancies, while neonatal complications occurred in 27%. In a report of 23 children followed up to 4 years, postnatal development was said to be normal. Blood pressure and renal function for these children were reported as normal (Prod Info Sandimmune(R) oral capsules, oral solution, intravenous injection, 2010; Prod Info NEORAL(R) MODIFIED oral capsules, solution, 2009).

B) ANIMAL STUDIES

1) FETOTOXICITY

a) RATS, RABBITS: Embryo and fetotoxicity were observed when pregnant rats and rabbits were given 30 to 100 mg/kg/day, but teratogenic effects were not seen (Ryffel, 1982).

3.20.3)

A) FETAL LOSS

1) According to the manufacturer, the outcomes of 116 pregnancies in women receiving cycloSPORINE , most throughout the entire gestational period of pregnancy, 90% of whom were transplant patients, have been reported. Sixteen fetal losses were reported, and 85 of the 100 pregnancies were complicated by disorders (eg, fetoplacental dysfunction, Rh incompatibility, premature labor, abruptio placentae, pre-eclampsia, eclampsia, and oligohydramnios). Almost half of the pregnancies (47%) resulted in preterm delivery. Five viable infants and 2 cases of fetal loss were reported to have malformations (Prod Info Sandimmune(R) oral capsules, oral solution, intravenous injection, 2010; Prod Info NEORAL(R) MODIFIED oral capsules, solution, 2009).

B) WEIGHT LOSS

1) A female renal transplant patient who received cycloSPORINE 175 mg/day orally throughout pregnancy and lactation delivered a healthy infant weighing 3.4 kg. However, the infant lost more than 10% of her birth weight during the first week (Osadchy & Koren, 2011).

C) PREGNANCY CATEGORY

1) CycloSPORINE is classified as FDA pregnancy category C (Prod Info Sandimmune(R) oral capsules, oral solution, intravenous injection, 2010).

3.20.4)

A) BREAST MILK

1) Serum levels in a breast-fed infant exposed to cycloSPORINE from the second trimester through the postpartum period were less than 30 nanogram (ng)/mL (below the detectable lower limit of normal) after morning feedings, with no adverse effects or toxicity noted. The 36-year-old mother was treated with cycloSPORINE IV and oral 5 mg/kg/day at week 26 of pregnancy for a severe ulcerative colitis flare unresponsive to steroid therapy. Trough serum levels ranged between 113 to 330 ng/mL and 73 to 152 ng/mL until delivery at 37 weeks and during breastfeeding, respectively. Infant monitoring was discontinued, the mother was transitioned to azathioprine, and mother and infant remained healthy at the 3-month follow-up (Lahiff & Moss, 2011).
2) Infant plasma cycloSPORINE levels were undetectable following maternal cycloSPORINE use throughout lactation. A female renal transplant patient being treated with cycloSPORINE 175 mg/day (2.1 mg/kg/day) orally had a blood concentration of cycloSPORINE of 49 mcg/L at 1 hour post-dose and a breast-milk concentration of 46 mcg/L at 2 hours post-dose, with a calculated milk-to-maternal blood ratio of 0.94. The estimated cycloSPORINE dose to which the infant would be exposed if breastfed 150 mL/kg of milk daily is 0.007 mg/kg, which is 0.33% of the weight-adjusted maternal dose. The concentration of cycloSPORINE in the infant's blood was an undetectable level (less than 10 mcg/L); thus, it was recommended in this case that the mother keep breastfeeding while continuing clinical observation for signs of cycloSPORINE toxicity (Osadchy & Koren, 2011).
3) There are no adequate or well controlled studies published that determine if cycloSPORINE is excreted in human milk after topical treatment. CycloSPORINE ophthalmic emulsion appears safe during the breastfeeding period as blood levels of the drug are undetectable following single or repeated application (Prod Info RESTASIS(R) ophthalmic emulsion, 2010).
4) CycloSPORINE is distributed into breast milk (Prod Info Sandimmune(R) oral capsules, oral solution, intravenous injection, 2010; Prod Info NEORAL(R) MODIFIED oral capsules, solution, 2009). The milk/plasma ratio and oral bioavailability are low and moderate, respectively; however, the possible risk to the infant still outweighs the benefits of breastfeeding. Even if the drug did not enter the breast milk, the increased energy and nutrient requirements for milk production could negatively impact the mother's recovery (Dillon et al, 1997).
5) CycloSPORINE was non-detectable in the blood of an infant receiving only breast-feedings from his mother for 10.5 months while she received therapeutic immunosuppression after kidney and pancreas transplantation. CycloSPORINE concentrations were measured simultaneously in infant whole blood, maternal whole blood, and breast milk at 23 days, 6.5 weeks, 9.7 weeks, 4 months, and 10.5 months after birth. Maternal serum cycloSPORINE concentrations ranged from 123 to 273 nanograms/mL, and breast milk concentrations exhibited a mean breast milk-to-maternal whole blood ratio of 84%. The infant did not show signs of cycloSPORINE-related toxicity; he subsequently attained the 46th and 55th percentiles for weight and height, respectively, at 12 months of age (Thiagarajan et al, 2001).
6) A woman receiving cycloSPORINE to prevent rejection of a renal allograft, breastfed her daughter and son without adverse effects in the infants. The daughter was breastfed completely until weaning and partially until she was 14 months old. At 5 weeks of age, the infant and maternal blood concentration of cycloSPORINE was less than 3 mcg/L and 260 mcg/L, respectively. Corresponding milk cycloSPORINE concentrations varied but averaged 596 mcg/L. The infant maintained normal renal function. At 2 years, her daughter was healthy and appeared to have no adverse effects related to cycloSPORINE exposure (Thiru et al, 1997).

3.20.5)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info Sandimmune(R) oral capsules, oral solution, intravenous injection, 2010).

B) ANIMAL STUDIES

1) RATS: Studies in male and female rats found no evidence of impairment of fertility (Prod Info Sandimmune(R) oral capsules, oral solution, intravenous injection, 2010).
2) RATS: No impairment in fertility was demonstrated in studies in male and female rats receiving oral doses of cycloSPORINE up to 15,000 times the human ophthalmic dose (Prod Info RESTASIS(R) ophthalmic emulsion, 2010).

Carcinogenicity

3.21.3)

A) LYMPHOMA-LIKE DISORDER

1) Immunosuppression with cycloSPORINE alone or in combination with other immunosuppressant agents has resulted in development of lymphoproliferative disorders and lymphomas (Calne et al, 1979; Bieber et al, 1980).

a) Of 2,521 organ transplant recipients who developed cancer, 130 were treated with cycloSPORINE (only 7 as sole therapy). Lymphomas were the most common type, occurring an average of 11 months following transplantation (Penn, 1987).

B) LACK OF EFFECT

1) CycloSPORINE does not appear to be mutagenic or tumorigenic in vitro (Matter et al, 1982).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor serum electrolytes, especially magnesium and potassium.
B) Monitor renal function, liver enzymes, and CBC with differential.
C) Measure triglycerides.
D) Institute continuous cardiac monitoring and obtain an ECGConsider obtaining acetaminophen or salicylate concentrations if there is any uncertainty regarding drug ingested.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Obtain and follow renal function parameters, such as BUN and serum creatinine.
2) Monitor liver enzymes.
3) Obtain serum electrolytes, particularly potassium and magnesium.
4) Measurement of glomerular filtration rate by insulin clearance was a more sensitive monitoring parameter for detection of chronic nephropathy than was serum creatinine in a study of heart transplant recipients (Tomlanovich et al, 1986).
5) Moyer et al (1988) reported that renal toxicity was minimized by using cycloSPORINE dosages that provided trough whole blood concentrations of 150 to 250 ng/mL (measured by HPLC) for the first four months of therapy, and 80 to 200 ng/mL thereafter (Moyer et al, 1988).
6) Measure triglycerides.

B) HEMATOLOGIC

1) Monitor CBC with differential.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor blood pressure following overdose or as indicated.
b) Institute continuous cardiac monitoring and obtain an ECG.

Methods

1) A commercial radioimmunoassay that measures parent drug and metabolites is available from Sandoz. Levels obtained by high performance liquid chromatography (HPLC) reflect only the parent drug (Carruthers et al, 1983).
2) Serum levels obtained by RIA were 1.7 times that of simultaneous serum HPLC levels in one patient (Schroeder et al, 1986).
3) Kyne et al (1990) described the use of high pressure liquid chromatography (parent compound only) and radioimmunoassay (which measures the parent compound and also cross-reacts with some of the many metabolites of the drug) to monitor cycloSPORINE concentrations in post heart transplant patients receiving daily cycloSPORINE (Kyne et al, 1990).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Symptomatic patients requiring ongoing supportive care may need admission. Once asymptomatic for 6 hours, they may be discharged.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients with unintentional ingestions may be observed at home if asymptomatic.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Severe poisoning may occur with large oral or parenteral exposures of cycloSPORINE. If concerned, consult a medical toxicologist for guidance. Consult specialists if hepatotoxicity, renal toxicity, or neurologic symptoms persist.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Symptomatic patients and those with deliberate ingestions should be evaluated in a healthcare facility. Patients who have minimal symptoms 6 hours after ingestion may be discharged.

Monitoring

Oral Exposure

6.5.1)

A) Generally, no decontamination is needed in the prehospital setting

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

3) Multiple-dose activated charcoal therapy has been used in one reported overdose case and resulted in an apparent change in cycloSPORINE half-life, from 9 hours (after discontinuation of charcoal) to 2.7 hours (during charcoal) (Honcharik & Anthone, 1985). There is insufficient evidence to support the routine use of activated charcoal for cycloSPORINE overdose at this time.

6.5.3)

A) SUPPORT

1) Treatment is primarily symptomatic and supportive.

B) MONITORING OF PATIENT

1) Monitor serum electrolytes, especially magnesium and potassium.
2) Monitor renal function, liver enzymes, and CBC with differential.
3) Measure triglycerides.
4) Institute continuous cardiac monitoring and obtain an ECG.
5) Consider obtaining acetaminophen or salicylate concentrations if there is any uncertainty regarding drug ingested.

C) HYPOMAGNESEMIA

1) Correct magnesium deficits.

D) HYPERKALEMIA

1) Treat severe hyperkalemia (associated dysrhythmias, QRS widening) aggressively. Monitor ECG continuously during and after therapy.
2) CALCIUM CHLORIDE

a) Intravenous calcium has no effect on circulating potassium levels, but it antagonizes cardiac toxicity in patients demonstrating cardiac signs and/or symptoms of hyperkalemia.
b) Use 10% calcium chloride.
c) ADULT DOSE: 5 to 10 mL (500 to 1000 mg) IV over 1 to 5 minutes; may repeat after 10 minutes (Saxena, 1989; Anon, 2000).
d) PEDIATRIC DOSE: 0.2 mL/kg (20 to 30 mg/kg per dose up to a maximum single dose of 5 mL (500 mg) IV over 5 to 10 minutes, repeated up to 4 times or until serum calcium increases (Barkin, 1986; Anon, 2000).
e) CALCIUM FOR INJECTION is available as 3 salts; calcium chloride, calcium gluconate, and calcium gluceptate.

1) While the other salts may be used, calcium chloride is the preferred salt for resuscitation since it directly delivers ionized calcium, whereas the other salts must be hepatically metabolized to release ionized calcium (Chameides, 1988).
2) Calcium chloride is very irritating, and should only be given via a central venous catheter. It may cause hypotension and bradycardia. Calcium salts are incompatible with bicarbonate (Chameides, 1988; Saxena, 1989; Anon, 2000).

3) INSULIN/DEXTROSE

a) Insulin enhances intracellular potassium shift.
b) ADULT DOSE: Administer 25 g of dextrose (250 mL of a 10% solution) IV over 30 minutes, and then continue the infusion at a slower rate.

1) Ten units of regular insulin are given subQ or added to the infusion.

c) ALTERNATIVE DOSE: 50 mL of a 50% dextrose solution with 5 to 10 units of regular insulin may be administered IV over 5 minutes.

1) Typically, this regimen will lower serum potassium by 1 to 2 mEq/L within 30 to 60 minutes with the decrease lasting for several hours (Saxena, 1989).

d) PEDIATRIC DOSE: 0.5 to 1 g/kg/dose followed by 1 unit of regular insulin IV for every 4 grams of glucose infused; may repeat every 10 to 30 minutes (Barkin, 1986).
e) HYPEROSMOLARITY: It must be remembered that 50% dextrose, and even 25% dextrose, are very hyperosmolar and may be sclerosing to peripheral veins (Chameides, 1988); administration of hypertonic solutions via central lines is preferred, if possible.

E) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

F) TOXIC NEPHROPATHY

1) DOPAMINE

a) Low dose dopamine infusion, 2 milligrams/kilogram/minute, completely reversed cycloSPORINE-induced renal dysfunction in 8 healthy volunteers given 12 milligrams/kilogram orally. Dopamine had no effect on blood pressure or heart rate (Conte et al, 1989).

G) PLASMA EXCHANGE

1) Valbonesi et al (1988) reported successful treatment of symptomatic hypertriglyceridemia with plasma exchange (Valbonesi et al, 1988).

a) Plasma triglycerides peaked at 3,215 milligrams/deciliter, at which time 3,200 milliliters of plasma were exchanged with 3.8% albumin.
b) The procedure was repeated four days later, and the patient remained asymptomatic and made an uneventful recovery despite a plasma triglyceride rebound of 1,530 milligrams/deciliter.

Eye Exposure

6.8.1)

A) Flush the eye copiously with tepid tap water or saline with at least 1 liter per eye.

6.8.2)

A) SUPPORT

1) CycloSPORINE also comes as an ophthalmic solution used to treat dry eyes and may increase the risk of an ocular infection. Flush the eye copiously with tepid tap water or saline with at least 1 liter per eye. Consider using local anesthetic drops for pain control and to ease irrigation.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) CycloSPORINE is minimally dialyzable and is NOT easily cleared by charcoal hemoperfusion (Prod Info Sandimmune(R) oral capsules, oral solution, intravenous injection, 2012).
2) In a study of 5 liver transplant patients, a 4-hour run of hemodialysis removed less than 1% of a 100 to 200 mg dose of cycloSPORINE. The total body clearance while on dialysis was not significantly different as compared to being off dialysis (Venkataramanan et al, 1984).

1) A 55-year-old man was inadvertently given a 50-fold oral overdose of cycloSPORINE, resulting in a serum cycloSPORINE concentration of 8,900 ng/mL. He was treated with whole blood exchange with erythrocyte apheresis on the first day (using 7 units of leukocyte-depleted RBCs), followed by plasma exchange (using 15 units (about 2,100 ml) of fresh frozen plasma) daily for 3 days. CycloSPORINE concentration decreased to 1470.6 ng/mL after the first whole blood exchange, and to 475.1 ng/mL after the third plasma exchange. He developed transient elevations in serum bilirubin and creatinine, but survived (Kwon et al, 2006).

Abstracts

Case Reports

1) A 32-year-old renal transplant patient inadvertently received 5000 mg of cyclosporin instead of 250 mg. Three hours later activated charcoal 60 g was given, followed by 30 g every 4 hours for 2 doses. The only effect from the overdose was a small increase in serum creatinine (from 1.6 to 1.9 mg/dL) (Honcharik & Anthone, 1985).
2) A 31-year-old renal transplant patient experiencing acute allograft rejection, who unintentionally ingested 5000 mg (92.6 mg/kg) of cycloSPORINE, acutely developed severe headache, intractable nausea, and a feeling of drunkenness, which resolved within 72 hours. The only biochemical change was a slight rise in BUN and serum creatinine (from 72 mg/dL to 85 mg/dL, and from 2.8 ng/dL to 3.5 ng/dL, respectively), (Schroeder et al, 1986).
3) A 43-year-old man with multiple sclerosis took 25 g of cycloSPORINE over 8 days. On the eighth day he developed a burning sensation in the mouth and feet, altered taste, hyperaesthesia of the hands, sore gums, facial flushing, foot swelling, and abdominal discomfort. There was no significant change in serum creatinine and no evidence of renal or liver dysfunction. There was a mild increase in blood pressure, from 110/65 mmHg to 160/100 mmHg. All signs and symptoms resolved within 2 weeks of discontinuation of cycloSPORINE, and without specific treatment (Baumhefner et al, 1987).
4) Accidental intravenous injection of 250 mg (6.25 mg/kg) in less than 30 minutes to a 23-year-old woman with Hodgkin's disease resulted in anxiety, diarrhea, vomiting, perspiration, and irregular pulse within 15 minutes of injection. Atrial fibrillation was noted two hours after injection. Because of the number of other medications administered (ornipressin, amphotericin B, MOPP, benzodiazepines, dexchlorpheniramine) these signs cannot be totally attributed to the cycloSPORINE. The decreased urine flow and increased BUN over the next 36 hours may have been due to the cycloSPORINE (Wallemacq & Lesne, 1985).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) IMPORTANT NOTE: Both Gengraf(TM) and Neoral(R) (cycloSPORINE modified) have increased bioavailability compared with Sandimmune(R) (non-modified). They are NOT bioequivalent and cannot be used interchangeably without physician supervision (Prod Info GENGRAF(R) oral capsules, 2012; Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2013).
B) INDICATION

1) TRANSPLANT REJECTION, TREATMENT AND PROPHYLAXIS

a) ORAL: Recommended initial dose is 15 mg/kg as a single dose 4 to 12 hours before cardiac, liver, or renal transplant; continue same dose as daily dose for 1 to 2 weeks and then decreased by 5% per week to a maintenance dose of 5 to 10 mg/kg/day (Prod Info Sandimmune(R) oral soft gelatin capsules, oral solution, intravenous injection, 2013; Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2013; Prod Info GENGRAF(R) oral solution, 2010; Prod Info GENGRAF(R) oral capsules, 2010).
b) In renal transplantation, initial oral doses as low as 10 to 14 mg/kg/day have been used (Prod Info Sandimmune(R) oral soft gelatin capsules, oral solution, intravenous injection, 2013).
c) INJECTION: Recommended initial dose of 5 to 6 mg/kg/day as a single dose 4 to 12 hours before cardiac, liver, or renal transplant; continue same initial dose as daily dose until patient can tolerate oral formulation (Prod Info Sandimmune(R) oral soft gelatin capsules, oral solution, intravenous injection, 2013).
d) One study found that renal toxicity was minimized by doses resulting in trough whole blood cycloSPORINE concentrations of 150 to 250 nanograms (ng)/mL (quantitated via HPLC) during the first months of therapy, and 80 to 200 ng/mL thereafter (Moyer et al, 1988).

2) PLAQUE PSORIASIS (SEVERE), RECALCITRANT

a) ORAL: Initial recommended dose of 2.5 mg/kg/day divided twice daily; after 4 weeks, dose may be increased 0.5 mg/kg/day at 2-week intervals; MAX: 4 mg/kg/day (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2013; Prod Info GENGRAF(R) oral solution, 2010; Prod Info GENGRAF(R) oral capsules, 2010).

3) RHEUMATOID ARTHRITIS (SEVERE)

a) ORAL: Initial recommended dose of 2.5 mg/kg/day divided twice daily; dose may be increased by 0.5 to 0.75 mg/kg/day at 8 weeks and 12 weeks; MAX: 4 mg/kg/day (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2013; Prod Info GENGRAF(R) oral solution, 2010; Prod Info GENGRAF(R) oral capsules, 2010)

4) KERATOCONJUNCTIVITIS SICCA

a) OPHTHALMIC: Instill 1 drop twice daily in each eye approximately 12 hours apart (Prod Info RESTASIS(R) ophthalmic emulsion, 2012).

7.2.2)

A) INDICATION

1) TRANSPLANT REJECTION, TREATMENT AND PROPHYLAXIS

a) There have been no reports of unusual adverse effects in pediatric patients as young as 6 months (Sandimmune(R)) and 1 year (Gengraf(R) and Neoral(R)) of age who have received cycloSPORINE; however, there are no adequate or well-controlled studies in the pediatric population (Prod Info Sandimmune(R) oral soft gelatin capsules, oral solution, intravenous injection, 2013; Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2013; Prod Info GENGRAF(R) oral solution, 2010; Prod Info GENGRAF(R) oral capsules, 2010).
b) ORAL: Recommended initial dose of 15 mg/kg administered 4 to 12 hours before cardiac, liver, or renal transplant or postoperatively; continue same dose as daily dose for 1 to 2 weeks and then decreased by 5% per week to maintenance dose of 5 to 10 mg/kg/day (Prod Info Sandimmune(R) oral soft gelatin capsules, oral solution, intravenous injection, 2013; Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2013; Prod Info GENGRAF(R) oral solution, 2010; Prod Info GENGRAF(R) oral capsules, 2010).
c) In renal transplantation, initial oral doses as low as 10 to 14 mg/kg/day have been used (Prod Info Sandimmune(R) oral soft gelatin capsules, oral solution, intravenous injection, 2013).

2) PSORIASIS

a) Safety and effectiveness have not been established in pediatric patients younger than 18 years of age (Prod Info NEORAL(R) oral soft gelatin capsules, oral solution, 2013; Prod Info GENGRAF(R) oral solution, 2010; Prod Info GENGRAF(R) oral capsules, 2010).

3) JUVENILE RHEUMATOID ARTHRITIS

4) KERATOCONJUNCTIVITIS SICCA

a) OPHTHALMIC:

1) 16 YEARS AND OLDER: Instill 1 drop twice daily in each eye approximately 12 hours apart (Prod Info RESTASIS(R) ophthalmic emulsion, 2012).
2) YOUNGER THAN 16 YEARS: Safety and efficacy have NOT been established in this age group (Prod Info RESTASIS(R) ophthalmic emulsion, 2012).

Minimum Lethal Exposure

1) ADULT

a) A 51-year-old man undergoing lung transplantation for pulmonary fibrosis inadvertently received an infusion of cycloSPORINE at a rate of 30 mg/hour (instead of 3 mg/hour) for 13 hours immediately post-op. Within 8 hours of stopping the infusion the patient died from brainstem compression; postmortem findings were consistent with diffuse cerebral edema with herniation of the cerebellar tonsils (De Perrot et al, 2000).

Maximum Tolerated Exposure

1) ORAL

a) ADULT

1) SUMMARY: Based on current information, cycloSPORINE does not appear to be highly toxic orally. Doses of 30 to 400 mg/kg produced only minor symptoms (Arellano et al, 1991).
2) Adults ingesting 5 g acutely, or 25 g over 8 days, have not developed serious toxicity (Honcharik & Anthone, 1985; Baumhefner et al, 1987).

b) CHILDREN

1) SUMMARY: Oral doses of 46 to 104 mg/kg have resulted in only minor toxicity.
2) A 3-year-old child was given 600 mg orally (46 mg/kg), a ten-fold overdose. No toxic clinical or laboratory effects were observed (de Meer et al, 1989).
3) A 2-month-old child was given 500 mg orally (104 mg/kg) and developed a transient rise in blood pressure (peak 109/77 mmHg) with no other toxic effects (de Meer et al, 1989).

2) PARENTERAL

a) ADULTS

1) A 30 mg/kg intravenous infusion was fairly well tolerated by one adult, resulting in only abdominal pain and increased bilirubin (Kokado et al, 1989).

b) CHILDREN

1) SUMMARY: Neonates receiving 179 to 400 mg/kg IV developed severe metabolic acidosis, cyanosis, and acute kidney failure (Arellano et al, 1991).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) Therapeutic trough blood concentrations are 250 to 800 ng/mL (RIA).
2) Therapeutic trough plasma concentrations are 50 to 300 ng/mL (done by RIA).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) ADULTS

1) A 51-year-old man undergoing lung transplantation for pulmonary fibrosis, inadvertently received an infusion of cycloSPORINE at a rate of 30 mg/hour (instead of 3 mg/hr) for 13 hours immediately post-op. Within 8 hours of stopping the infusion the patient died from brainstem compression. Based on pharmacodynamic calculations, a level of 1700 nanograms/milliliter may have been reached before the drug was withdrawn (De Perrot et al, 2000).
2) Following an inadvertent 1000 mg oral dose, a 61-year-old man was reported to have a serum cycloSPORINE level of 2438 nanograms/milliliter (normal 100 to 300 ng/mL) at 60 minutes postingestion (LoVecchio & Curry, 1998).
3) In a polydrug overdose by a 60-year-old renal transplant patient, it was determined that cycloSPORINE 10 grams had been ingested with a total cycloSPORINE blood level of 1800 ng/mL reported. Minimal alterations in renal, liver, or neurological function developed (Zylber-Katz et al, 1994).
4) A 43-year-old man who took 25 g over 8 days had a blood level of 1778 ng/mL (plasma level 968 ng/mL) the day following discontinuation (Baumhefner et al, 1987).
5) A 32-year-old man who overdosed on 5 g had a plasma level of 6700 ng/mL at 4 hours, 675 ng/mL at 13 hours, and 50 ng/mL at 47 hours after ingestion. Levels were measured by the RIA method. No symptoms resulted (Honcharik & Anthone, 1985).

b) PEDIATRIC

1) A 3-year-old child who received 600 mg orally had a peak plasma level 459 mcg/L after 5 hours (de Meer et al, 1989).
2) A 2-month-old child who received 500 mg orally had a peak plasma level of 447 mcg/L after 6 hours (de Meer et al, 1989).

2) DISEASE STATE

a) THERAPEUTIC USE

1) Nephrotoxicity is most likely to occur in patients with trough plasma concentrations (done by RIA) of greater than 500 nanograms/milliliter (Howes et al, 1983).
2) Some studies involving renal transplant patients have shown that 96% of patients with cycloSPORINE-nephropathy have trough plasma levels greater than or equal to 250 ng/mL (Gordon et al, 1985).

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (ORAL)MOUSE:

a) 2329 mg/kg (RTECS , 2000)

2) LD50- (ORAL)RAT:

a) 1480 mg/kg (RTECS , 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

1) In animal models, cycloSPORINE produces evidence of structural renal damage within 4 days of receiving oral doses of more than 25 mg/kg/day. Structural damage is generally confined to the descending limb of the loop of Henle in the proximal tubule. Stimulation of the renin-angiotenson-aldosterone system may play a part (Thomson et al, 1984).
2) Daily administration of 50 mg/kg to rats results in increased plasma renin activity by day 4 (Whiting et al, 1985).
3) The effects of cycloSPORINE on renal function were primarily due to renal vasoconstriction in one study (Conte et al, 1989).

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.12)

A) Oral administration of 50 mg/kg/day consistently produced nephrotoxic and hepatotoxic effects in rats (Duncan et al, 1986).

References

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CYCLOSPORINE

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General Bibliography