Cyclosporin A

1202.61

1201.841309

200-835-2

DTXSID0020365

Forms white prismatic crystals from acetone

2941909000

279 Ų

2.92 (LogP)

white solid

1.0±0.1 g/cm3

148-151°C

1293.8°C at 760 mmHg

87℃

1.468

soluble in dimethyl sulfoxide and ethanol. Insoluble in water.ethanol: 30 mg/mL

2-8°C

LD50 in mice, rats, rabbits (mg/kg): 107, 25, >10 i.v.; 2329, 1480, >1000 orally (Ryffel)

D20 -244° (c = 0.6 in chloroform); D20 -189° (c = 0.5 in methanol)

Slightly water soluble (NTP, 1992).

Amides and Imides

CYCLOSPORIN A is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

UN 1648 3 / PGII

3

45-60-22-40-36-20/21/22-11

53-45-36/37-24/25-22-26-16

GZ4120000

T,Xn,F

P201-P301 + P312 + P330-P308 + P313

H302-H350-H360

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Non-PVC containers & administration sets should be used to administer cyclosporine solns. ... Use of glass containers & tubing that does not contain DEHP to administer cyclosporine was recommended.

National Toxicology Program. Eleventh Report on Carcinogens (2005). The Report on Carcinogens is an informational scientific and public health document that identifies and discusses substances (including agents, mixtures, or exposure circumstances) that may pose a carcinogenic hazard to human health. Cyclosporin A (59865-13-3) is listed as known to be a human carcinogen.[Available from, as of July 31, 2009: http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s053cycl.pdf]

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

|Danger|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P281, P301+P312, P308+P313, P314, P330, P405, and P501|Aggregated GHS information provided by 341 companies from 16 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this material in a refrigerator. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

In several large clinical trials, initiation of cyclosporine therapy was associated with mild elevations in serum bilirubin levels, often without significant increases in serum ALT or alkaline phosphatase. Elevations in serum enzymes were also described, but less commonly. Recently, these complications appear to be less frequent, perhaps because of more careful dosing and monitoring of cyclosporine levels. Furthermore, in treatment of autoimmune diseases without the many complications of transplantation, cyclosporine therapy has been associated with mild serum alkaline phosphatase elevations in up to 30% of patients, but the abnormalities are asymptomatic, usually self-limiting and rarely require dose adjustment. In several case series, cyclosporine therapy has also been associated with biliary sludge and cholelithiasis. Isolated case reports of clinically apparent acute liver injury have been attributed to cyclosporine. The time to onset was within a few weeks of starting cyclosporine and the pattern of serum enzyme elevations was cholestatic. Recovery was prompt once cyclosporine was stopped and cases of chronic hepatitis or acute liver failure due to cyclosporine have not been reported.|In large randomized controlled trials of voclosporin, serum aminotransferase levels were transiently elevated in 3% of patients, but rates were similar in controls receiving conventional therapy (2%). Similar to cyclosporine, voclosporin therapy is associated with minor increases in alkaline phosphatase and bilirubin levels, although values usually remain within the normal range. In the prelicensure studies of voclosporin, there were no instances of clinically apparent liver injury attributable to therapy. Clinical experience with this agent, however, has been limited and other calcineurin inhibitors have been found to cause rare instances of hepatic injury, which are generally cholestatic, mild-to-moderate in severity and self-limited in course once treatment is stopped.

Cyclosporine interacts with a wide variety of commonly used drugs, & close attention must be paid to drug interactions. Any drug that affects microsomal enzymes, especially the CYP3A system, may affect cyclosporine blood concns. Substances that inhibit this enzyme can decr cyclosporine metab & incr blood concns. These include calcium channel blockers (e.g., verapamil, nicardipine), antifungal agents (e.g., fluconazole, ketoconazole), antibiotics (e.g., erythromycin), glucocorticoids (e.g., methylprednisolone), HIV-protease inhibitors (e.g., indinavir), & other drugs (e.g., allupurinol & metoclopramide). In addition, grapefruit & grapefruit juice block the CYP3A system & incr cyclosporine blood concns & thus should be avoided by patients receiving the drug. In contrast, drugs that induce CYP3A activity can incr cyclosporine metab & decr blood concns. Drugs that can decr cyclosporine concns in this manner include antibiotics (e.g., nafcillin & refampin), anticonvulsants (e.g., phenobarbital, phenytoin), & other drugs (e.g., octreotide, ticlopidine). In general, close monitoring of cyclosporine blood levels & the levels of other drugs is required when such combinations are used. Interactions between cyclosporine & sirolimus have led to the recommendation that admin of the two drugs be separated by time. Sirolimus aggravate cyclosporine-induced renal dysfunction, while cyclosporine increases sirolimus-induced hyperlipemia & myelosuppression. Other cyclosporine-drug interactions of concern include additive nephrotoxicity when coadministered with nonsteroidal antiinflammatory drugs & other drugs that cause renal dysfunction; elevation in methotrexate levels when the two drugs are coadministered; & reduced clearance of other drugs, including prednisolone, digoxin, & lovastatin.|Cyclosporine increases the volume of distribution, half-life, & renally eliminated fraction of digoxin. Cyclosporine potentiates vecuronium blockade & prolongs recovery time. Drugs with clinically established effects on cyclosporine metab are/: calcium channel blockers, Diltiazepam, Nifedipine, Verapamil, Ceftriaxone, Erythromycin, Norfloxacin, Ketoconazole, Fluconazole, Ciprofloxacin, Josamycin, Methyltestosterone, Omeprazole, Sulindac, Sex hormones, Corticosteroids, Metolazone, Acetazolamide, Alcohol, Cimetidine, Danazol, Imipenem/cilastin, Itraconazole, Oral contraceptives, Pristinamycin- Incr blood cyclosporine levels; Sulfadimidine, Phenytoin, Phenobarbital, Primidone, Carbamazepine, Rifampin, Ethambutol, Isoniazid, Quinine, Griseofulvin, Rifamycin, Warfarin, Chlorambucil- Decr blood cyclosporine levels/. /From table/|/Concurrent use with allopurinol, androgens, bromocriptine, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, estrogens, fluconazole, HIV protease inhibitors, itraconazole, ketoconazole, metoclopramide, miconazole, nefazodone, nicardipine, verapamil/ may increase blood concentrations of cyclosporine by inhibiting cytochrome p450 3A enzymes, and may increase the risk of hepatotoxicity and nephrotoxicity; because of its similarity to ketoconazole, miconazole may be expected to have the same effect; although concurrent use of HIV protease inhibitors and cyclosporine have not been studied, HIV protease inhibitors are known to inhibit cytochrome p450 3A enzymes; frequent monitoring of blood cyclosporine concentrations and hepatic and renal function may be needed if these drugs are used concurrently with cyclosporine.|Concurrent use of NSAIDs, especially indomethacin, with cyclosporine may increase the risk of renal failure; concurrent administration with cyclosporine may also result in hyperkalemia; additive decreases in renal function have been reported with concurrent use of diclofenac or naproxen with cyclosporine.|For more Interactions (Complete) data for CYCLOSPORIN A (20 total), please visit the HSDB record page.

LD50 Rat oral 1489 mg/kg|LD50 Rat ip 147 mg/kg|LD50 Rat sc 286 mg/kg|LD50 Rat iv 24 mg/kg|For more Non-Human Toxicity Values (Complete) data for CYCLOSPORIN A (7 total), please visit the HSDB record page.

... A dose range-finding study /was/ ... performed in order to determine doses /of cyclosporin A/ that could be used in a long term carcinogenesis study in a transgenic animal. ... Female C57BL/6 mice ... were treated with Cyclosporine A (CSA) for 6 alternating days over a 12-day period by oral gavage. ... The in-life phase of these studies was carried out between 18 September 1995 and 29 September 1995. In this study, body weights were not decreased and the only organ weight to show a change was the liver which was increased by as much as 16%. Cyclosporine A produced a biphasic response in the antibody-forming cell response to the T-dependent antigen sRBC. At a dose of 10 mg/kg there was a 60% enhanced response, while at the 100 mg/kg dose a 60% reduction in the immune response was seen.

Cyclosporine crosses the placenta & is distributed into milk.|Cyclosporine is excreted into human breast milk, but no reports of its use during breast feeding have been located. ... In another patient, milk concns 22 hr after a dose of 325 mg were 16 ng/ml while maternal blood levels were 52 ng/ml, a milk:plasma ratio of 0.31. A milk:plasma ratio of 0.40 was reported in one study, & a ratio of approximately 0.17 was measured in another. Breast feeding was not allowed in any of these studies & has been actively discouraged by most sources because of concerns for potential toxicity in the nursing infant. The American Academy of Pediatrics considers cyclosporine to be contraindicated during breast feeding due to the potential for immune suppression & neutropenia, an unknown effect on growth, & a possible association with carcinogenesis.

Cyclosporine is excreted into human breast milk, but no reports of its use during breast feeding have been located. ... In another patient, milk concns 22 hr after a dose of 325 mg were 16 ng/ml while maternal blood levels were 52 ng/ml, a milk:plasma ratio of 0.31. A milk:plasma ratio of 0.40 was reported in one study, & a ratio of approximately 0.17 was measured in another.

Cyclosporine is a calcineurin inhibitor and potent immunosuppressive agent used largely as a means of prophylaxis against cellular rejection after solid organ transplantation. Cyclosporine therapy can be associated with mild elevations in serum bilirubin and transient serum enzyme elevations, and to rare instances of clinically apparent cholestatic liver injury.|Voclosporin is an orally available calcineurin inhibitor and potent immunosuppressive agent which is used in combination with mycophenolate mofetil and corticosteroids to treat acute lupus nephritis. Voclosporin may be associated with low rate of transient serum enzyme elevations during treatment but has not been linked to instances of clinically apparent acute liver injury with jaundice.

Dermatologic Agents; Transplant Agents|Immunosuppressive Agents

Clinical indications for cyclosporine are kidney, liver, heart, & other organ transplantation; rheumatoid arthritis; & psoriasis. ... Cyclosporine usually is used in combination with other agents, especially glucocorticoids & either azathioprine or mycophenolate mofetil &, most recently, sirolimus. ... In rheumatoid arthritis, cyclosporine is used in cases of severe disease that have not responded to methotrexate. Cyclosporine can be used in combination with methotrexate, but the levels of both drugs must be monitored closely. In psoriasis, cyclosporine is indicated for treatment of adult nonimmunocompromised patients with severe & disabling disease who have failed other systemic therapies. Because of its mechanism of action, there is a theoretical bases for the use of cyclosporine in a variety of other T-cell-mediated diseases. Cyclosporine has been reported to be effective in Behcet's acute ocular syndrome, endogenous uveitis, atopic dermatitis, inflammatory bowel disease, & nephrotic syndrome when standard therapies have failed.|For prevention of allograft rejection in adults and children ... .|Cyclosporine is indicated, usually in combination with corticosteroids, for prevention of rejection of renal, hepatic, and cardiac transplants (allografts). /Included in US product labeling/|Cyclosporine is also indicated for prevention of rejection of heart-lung and pancreatic transplants. /NOT included in US product labeling/|For more Therapeutic Uses (Complete) data for CYCLOSPORIN A (13 total), please visit the HSDB record page.

Non-PVC containers & administration sets should be used to administer cyclosporine solns. ... Use of glass containers & tubing that does not contain DEHP to administer cyclosporine was recommended.|Cyclosporine is distributed into breast milk. Mothers taking cyclosporine should not breast-feed their babies, because of the potential risk of serious adverse effects (e.g., hypertension, nephrotoxicity, malignancy) in the infant.|Appropriate studies performed to date in pediatric patients receiving cyclosporine for organ transplantation have not demonstrated pediatrics-specific problems that would limit the usefulness of cyclosporine in children. Cyclosporine has been used in pediatric patients 1 year of age and older receiving organ transplantations. Pediatric patients have increased clearance of cyclosporine as compared with adult patients. The safety and efficacy of cyclosporine to treat psoriasis and rheumatoid arthritis in pediatric patients have not been established.|Geriatric patients were included in the clinical trials of cyclosporine to treat rheumatoid arthritis. Geriatric patients were more likely to experience hypertension and increases in serum creatinine concentrations than were younger adult patients.|For more Drug Warnings (Complete) data for CYCLOSPORIN A (30 total), please visit the HSDB record page.

Drugs used to treat or prevent skin disorders or for the routine care of skin. (See all compounds classified as Dermatologic Agents.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)|Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. (See all compounds classified as Antifungal Agents.)|Drugs that are used to treat RHEUMATOID ARTHRITIS. (See all compounds classified as Antirheumatic Agents.)|Compounds that inhibit or block the PHOSPHATASE activity of CALCINEURIN. (See all compounds classified as Calcineurin Inhibitors.)|Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. (See all compounds classified as Immunosuppressive Agents.)

Following oral admin of cyclosporine, the time to peak blood concns is 1.5-2.0 hr. Admin with food both delays & decreases absorption. High & low fat meals consumed within 30 min of admin decr the AUC by approx 13% & the max concn by 33%. This makes it imperative to individualize dosage regimens for outpatients. Cyclosporine is distributed extensively outside the vascular compartment. After iv dosing, the steady-state volume of distribution has been reported to be as high as 3-5 liters/kg in solid-organ transplant recipients. Only 0.1% of cyclosporine is excreted unchanged in urine. ... Cyclosporine & its metabolites are excreted principally through the bile into the feces, with only approx 6% being excreted in the urine. Cyclosporine also is excreted in human milk.|... Absorption of cyclosporine is incomplete following oral admin. The extent of absorption depends upon several variables, including the individual patient & formulation used. The elimination of cyclosporine form the blood is generally biphasic, with a terminal half-life of 5-18 hr. After iv infusion, clearance is approx 5-7 ml/min/kg in adult recipients of renal transplants, but results differ by age & patient populations. For example, clearance is slower in cardiac transplant patients & more rapid in children. The relationship between admin dose & the area under the plasma concn-vs-time curve is linear within the therapeutic range, but the intersubject variability is so large that individual monitoring is required.|Clinicians can administer cyclosporine by continuous iv infusion during the first few days after transplantation, then orally by twice-daily doses, to achieve plasma cyclosporine concns (measured by HPLC) of 75-150 ng/ml (equivalent to whole blood cyclosporine concns of 300-600 ng/ml measured by radioimmunoassay). It appears safe to maintain a trough plasma cyclosporine concn of about 75-150 ng/ml; however, this does not necessarily guarantee safety from nephrotoxicity. Because of preferential distribution of cyclosporine & its metabolites into red blood cells, blood levels are generally higher than plasma levels. When blood cyclosporine levels are 300-600 ng/ml by radioimmunoassay, cerebrospinal fluid levels range from 10-50 ng/ml. The apparent volume of distribution in children under 10 yr of age is about 35 l/kg, & in adults, 4.7 l/kg.|The elimination half-life of an oral cyclosporine dose of 350 mg is 8.9 hr; after a 1400 mg dose, the half-life is 11.9 hr. Elimination occurs predominantly by metab in the liver to form 18-25 metabolites. Metabolites of cyclosporine possess little immunosuppressive activity. Cyclosporine is extensively metabolized in the liver by cytochrome P450IIIA oxidase; however, neurotoxicity & possibly nephrotoxoicity usually correlate with raised blood levels of cyclosporine metabolites. Only 0.1% of a dose ix s excreted unchanged.|For more Absorption, Distribution and Excretion (Complete) data for CYCLOSPORIN A (7 total), please visit the HSDB record page.

Cyclosporine is extensively metabolized in the liver by the cytochrome-P450 3A (CYP3A) enzyme system & to a lesser degree by the GI tract & kidneys. At least 25 metabolites have been identified in human bile, feces, blood, & urine. Although the cyclic peptide structure of cyclosporine is relatively resistant to metab, the side chains are extensively metabolized. All of the metabolites have both reduced biological activity & toxicity compared to the parent drug.

Cyclosporine suppresses some humoral immunity but is more effective against T cell-dependent immune mechanisms such as those underlying transplant rejection & some forms of autoimmunity. It preferentially inhibits antigen-triggered signal transduction in T lymphocytes, blunting expression of many lymphokines, including /(interleukin-2)/ IL-2, as well as expression of antiapoptotic proteins. Cyclosporine forms a complex with cyclophilin, a cytoplasmic receptor protein present in target cells. This complex binds to calcineurin, inhibiting Ca2+ stimulated dephosphorylation of the cytosolic component of NFAT. When the cytoplasmic component of NFAT is dephosphorylated, it translocates to the nucleus, where it complexes with nuclear components required for complete T-cell activation, including transactivation of IL-2 & other lymphokine genes. Calcineurin enzymatic activity is inhibited following physical interaction with the cyclosporine/cyclophilin complex. This results in the blockade of NFAT dephosphorylation; thus, the cytoplasmic component of NFAT does not enter the nucleus, gene transcription is not activated, & the T lymphocyte fails to respond to specific antigenic stimulation Cyclosporine also increases expression of transforming growth fact /beta/ (TGF-B), a potent inhibitor of IL-2-stimulated T-cell proliferation & generation of cytotoxic T lymphocytes (CTL).|The exact mechanism of action is unknown but seems to be related to the inhibition of production and release of interleukin-2, which is a proliferative factor necessary for the induction of cytotoxic T lymphocytes in response to alloantigenic challenge, and which plays a major role in both cellular and humoral immune responses. Cyclosporine does not affect the nonspecific defense system of the most and does not cause significant myelosuppression.|The major pharmacodynamic action of cyclosporin within T cells is calcineurin inhibition. The complex cyclophilin-cyclosporin competitively binds to the Ca(2+)- & calmodulin-dependent phosphatase calcineurin which then inhibits downstream dephosphorylation & activation of NFAT(transcription factor). The greatest calcineurin inhibition is seen 1-2 hr after admin of Neoral in parallel to the highest blood concn.|Treatment of patients after organ transplantation with the immunosuppressive drug cyclosporin A (CsA) is often accompanied by impaired glucose tolerance, thus promoting the development of diabetes mellitus. ... /The authors/ show that 2-5 microM CsA diminishes glucose-induced insulin secretion of isolated mouse pancreatic islets in vitro by inhibiting glucose-stimulated oscillations of the cytoplasmic free-Ca(2+) concn [Ca(2+)](c). This effect is not due to an inhibition of calcineurin, which mediates the immunosuppressive effect of CsA, because other calcineurin inhibitors, deltamethrin & tacrolimus, did not affect the oscillations in [Ca(2+)](c) of the B-cells. The CsA-induced decr in [Ca(2+)](c) to basal values was not caused by a direct inhibition of L-type Ca(2+) channels. CsA is known to be a potent inhibitor of the mitochondrial permeability transition pore (PTP), which ... /the authors/ recently suggested to be involved in the regulation of oscillations. Consequently, CsA also inhibited the oscillations of the cell membrane potential, & it is shown that these effects could not be ascribed to cellular ATP depletion. However, the mitochondrial membrane potential Delta Psi was affected by CsA by inhibiting the oscillations in Delta Psi. ... The observed reduction in [Ca(2+)](c) could be counteracted by the K(+)(ATP) channel blocker tolbutamide, indicating that the stimulus-secretion coupling was interrupted before the closure of K(+)(ATP) channels. It is concluded that CsA alters B-cell function by inhibiting the mitochondrial PTP. This terminates the oscillatory activity that is indispensable for adequate insulin secretion. Thus, CsA acts on different targets to induce the immunosuppressive & the diabetogenic effect.|CsA increases CTGF, collagen I, & collagen III mRNA expressions in the heart. The induction of CTGF gene is mediated, at least in part, by angiotensin II.

SYMPTOMS: Symptoms of exposure to this compound include hepatotoxicity, nephrotoxicity, hyperkalemia, hyperuricemia, convulsions, renal dysfunction, tremor, hirsutism, hypertension, gum hyperplasia, cramps, acne, headache, diarrhea, nausea, vomiting, abdominal discomfort, paresthesia, flushing, leukopenia, lymphoma, sinusitis and gynecomastia. In 2% or less of persons exposed, it has caused allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia and tinnitus. Rare reactions include anxiety, chest pain, constipation, depression, hair breaking hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper gastrointestinal bleeding, visual disturbance, weakness and weight loss. It has caused kidney and liver damage. An increased susceptibility to infection may occur. Other symptoms include gastrointestinal disturbance, rashes and angioedema. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Supportive and symptomatic treatment should be initiated. Hemodialysis and charcoal hemoperfusion reportedly are not useful for enhancing the elimination of cyclosporine following overdosage. When overdosage occurs in patients prescribed cyclosporine therapy, the drug may be withheld for a few days or alternate -day therapy may be initiated until the patient is stabilized.

The principal adverse reactions to cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, hyperlipidemia, & gum hyperplasia. Nephrotoxicity is limiting & occurs in the majority of patients treated. It is the major indication for cessation or modification of therapy. Hypertension may occur in approx 50% of renal transplant & almost all cardiac transplant patients. Combined use of calcineurin inhibitors & glucocorticoids is particularly diabetogenic, with diabetes being more frequent in patients treated with tacrolimus than in those receiving cyclosporine.|Questionable human carcinogen producing Hodgkin's disease. ... Human systemic effects by ingestion: increased body temp, cyanosis.|An adult ingested 25,000 mg over 8 days & survived. Two adults & one child received 5000 mg of cyclosporine each by error & lived. A 37 yr old woman took 7500 mg in a suicide attempt & exhibited few symptoms. A 2 yr old received 240 mg, developed hypotension, wheezing, pallor, & tachycardia, & lived. A neonate received 400 mg/kg, developed cyanosis, metabolic acidosis, respiratory depression, & renal failure, & survived. Oral overdoses form 10-150 mg/kg were reported with only mild signs of toxicity. An adult received, by error, a 250 mg dose of iv cyclosporine in 30 min with ornithine-vasopressin &, within 15 min, developed anxiety & an irregular weak pulse. An adult accidentally received 30 mg/kg/day (1.1 mg/kg/hr) for 33 hr by iv infusion; he survived. The highest recorded total dose is approximately 10 g.|Cyclosporine crosses the placenta & is distributed into milk.|For more Human Toxicity Excerpts (Complete) data for CYCLOSPORIN A (8 total), please visit the HSDB record page.

Ciclosporin

Neoral is a microemulsion preconcentrate; a microemulsion is a mixture of the lipophilic active substance with accurately balanced amounts of lipophilic solvent, hydrophilic solvent & surfactant.