シクロスポリン

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.

/Cyclosporine/ should be stored below 30 °C & protected from light. Light protection is not required for iv admixtures of cyclosporine.

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.

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.

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.

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)

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 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.

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.

Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.

Cardiovascular: Hypertension, arrhythmia.

The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. The extent of absorption is dependent on the individual patient, the patient population, and the formulation. The absolute bioavailability of cyclosproine administered as Sandimmune™ is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients. The cyclosporine capsules and oral solution are bioequivalent. The time of peak blood concentrations (Tmax) following oral administration of cyclosporine [modified] ranged from 1.5 - 2.0 hours.

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.

In the event of toxicity, establishing a patent airway is a priority. There is a need to watch for signs of respiratory insufficiency and provide ventilation assistance if needed. Also, the healthcare provider needs to monitor for shock and treat if necessary. They should anticipate seizures and treat if necessary, and initiate supportive and symptomatic treatment. When overdosage occurs in patients prescribed cyclosporine therapy, the healthcare provider may withhold the drug for a few days or initiate alternate-day therapy until the patient stabilizes.

Cyclosporine binds to cyclophilin. The complex then inhibits calcineurin which is normally responsible for activating transcription of interleukin 2. Cyclosporine also inhibits lymphokine production and interleukin release. In ophthalmic applications, the precise mechanism of action is not known. Cyclosporine emulsion is thought to act as a partial immunomodulator in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=59865-13-3]

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

Group 1: Carcinogenic to humans

Volume 50: (1990) Pharmaceutical Drugs

2012

2008

1, carcinogenic to humans. (L135)

Drug Induced Liver Injury Rank (DILIrank 2.0)

Cyclosporine

vMost-DILI-concern

7

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

Produced by Tolypocladium inflatum and other fungi imperfecti; An immunosuppressant; Veterinary applications include control of immune-mediated dermatological diseases; [Merck Index] Used in organ transplantation; [HSDB] Used as an immunosuppressive drug since the 1980s; [IARC]

Used in organ transplantation

Immunosuppressant action directed mainly against T-lymphocytes resulting in inhibition of cell-mediated immunity and, to a lesser extent, antibody production.

Use (kg; approx.) in Germany (2009): >1000

For treatment of transplant (kidney, liver, and heart) rejection, rheumatoid arthritis, severe psoriasis.

Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients

Pharmaceuticals -> Animal Drugs -> Approved in Taiwan