Cyclosporin A

Slightly soluble (NTP, 1992)

insoluble

Slightly soluble in water and saturated hydrocarbons; very soluble in methanol, acetone, and diethyl ether

Sol in chloroform

27 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Antirheumatic Agents; Calcineurin Inhibitors; Immunosuppressive Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine (Orphan designations)

FDA approved drugs -> Active ingredient

Active Ingredients (Cyclosporine) -> FDA Greenbook

Pharmaceuticals -> Animal Drugs -> Approved in Taiwan

298 to 304 °F (NTP, 1992)

148-151 °C

148-151 °C

Cyclosporin a appears as white prismatic needles (from acetone) or white powder. (NTP, 1992)

White solid; [Merck Index] White powder; [MSDSonline]

Danger

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P264, P270, P280, P301+P317, P318, P319, P330, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 282 reports by companies from 18 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H302: Harmful if swallowed [Warning Acute toxicity, oral]

Hazard Traits - Carcinogenicity

Cyclosporine: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

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)

A nephrotoxin and hepatotoxin; [CAMEO] Directly toxic to the kidney; [Olson, p. 41] Causes chronic tubulointerstitial nephritis; [Ford, p. 194] In studies of rats, can cause male sterility and fetotoxicity at high doses; Enhances the development of lymphomas in animals and humans; [IARC] When used as a drug, nephrotoxicity occurs in all patients and is the limiting factor in its use. Nephrotoxicity is associated with trough plasma levels >250 ng/mL and hepatotoxicity with trough levels >1000 ng/mL; [HSDB]

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]

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).

Acute Tox. 4 (100%)

Acute toxicity (Oral) - Category 4

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

L04AD01

L - Antineoplastic and immunomodulating agents

S - Sensory organs

QL - Antineoplastic and immunomodulating agents

QS - Sensory organs

L04AD01

Cyclosporine exerts potent immunosuppressive actions on T cells, thereby prolonging survival following organ and bone marrow transplants. This drug prevents and controls serious immune-mediated reactions including allograft rejection, graft versus host disease, and inflammatory autoimmune disease. Some notable effects of cyclosporine are hypertrichosis, gingival hyperplasia, and hyperlipidemia. There is also some debate about this drug causing nephrotoxicity.

Cyclosporine is a calcineurin inhibitor that inhibits T cell activation. Its binding to the receptor cyclophilin-1 inside cells produces a complex known as cyclosporine-cyclophilin. This complex subsequently inhibits calcineurin, which in turn stops the dephosphorylation as well as the activation of the nuclear factor of activated T cells (NF-AT) that normally cause inflammatory reactions. NF-AT is a transcription factor that promotes the production of cytokines such as IL-2, IL-4, interferon-gamma and TNF-alpha, all of which are involved in the inflammatory process. Specifically, the inhibition of IL-2, which is necessary for T cell activation or proliferation, is believed to be responsible for cyclosporine's immunosuppressive actions. In addition to the above, the inhibition of NF-AT leads to lower levels of other factors associated with T helper cell function and thymocyte development.

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.

The half-life of cyclosporine is biphasic and very variable on different conditions but it is reported in general to last 19 hours. Prescribing information also states a terminal half-life of approximately 19 hours, but with a range between 10 to 27 hours.

Cyclosporine is metabolized in the intestine and the liver by CYP450 enzymes, predominantly CYP3A4 with contributions from CYP3A5. The involvement of CYP3A7 is not clearly established. Cyclosporine undergoes several metabolic pathways and about 25 different metabolites have been identified. One of its main active metabolites, AM1, demonstrates only 10-20% activity when compared to the parent drug, according to some studies. The 3 primary metabolites are M1, M9, and M4N, which are produced from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively.

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.

Hepatic, extensively metabolized by the cytochrome P450 3A enzyme system in the liver. It is also metabolized in the gastrointestinal tract and kidney to a lesser degree. The metabolites are significantly less potent than the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. Route of Elimination: Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Only 0.1% of the dose is excreted in the urine as unchanged drug. Half Life: Biphasic and variable, approximately 7 hours (range 7 to 19 hours) in children and approximately 19 hours (range 10 to 27 hours) in adults.

83HN0GTJ6D

CYCLOSPORINE

Established Pharmacologic Class [EPC] - Calcineurin Inhibitor Immunosuppressant

Mechanisms of Action [MoA] - Calcineurin Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors

Mechanisms of Action [MoA] - P-Glycoprotein 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.

Drugs used to treat or prevent skin disorders or for the routine care of skin.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

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.

Drugs that are used to treat RHEUMATOID ARTHRITIS.

Compounds that inhibit or block the PHOSPHATASE activity of CALCINEURIN.

The absorption of cyclosporine occurs mainly in the intestine. Absorption of cyclosporine is highly variable with a peak bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients. The absorption of cyclosporine from the GI tract has been found to be incomplete, likely due to first pass effects. Cmax in both the blood and plasma occurs at approximately 3.5 hours post-dose. The Cmax of a 0.1% cyclosporine ophthalmic emulsion is 0.67 ng/mL after instilling one drop four times daily. A note on erratic absorption During chronic administration, the absorption of Sandimmune Soft Gelatin Capsules and Oral Solution have been observed to be erratic, according to Novartis prescribing information. Those being administered the soft gelatin capsules or oral solution over the long term should be regularly monitored by testing cyclosporine blood concentrations and adjusting the dose accordingly. When compared with the other oral forms of Sandimmune, Neoral capsules and solution have a higher rate of absorption that results in a higher Tmax and a 59% higher Cmax with a 29 % higher bioavailability.

After sulfate conjugation, cyclosporine remains in the bile where it is broken down to the original compound and then re-absorbed into the circulation. Cyclosporine excretion is primarily biliary with only 3-6% of the dose (including the parent drug and metabolites) excreted in the urine while 90% of the administered dose is eliminated in the bile. From the excreted proportion, under 1% of the dose is excreted as unchanged cyclosporine.

The distribution of cyclosporine in the blood consists of 33%-47% in plasma, 4%-9% in the lymphocytes, 5%-12% in the granulocytes, and 41%-58% in the erythrocytes. The reported volume of distribution of cyclosporine ranges from 4-8 L/kg. It concentrates mainly in leucocyte-rich tissues as well as tissues that contain high amounts of fat because it is highly lipophilic. Cyclosporine, in the eye drop formulation, crosses the blood-retinal barrier.

Cyclosporin shows a linear clearance profile that ranges from 0.38 to 3 Lxh/kg, however, there is substantial inter- patient variability. A 250 mg dose of cyclosporine in the oral soft gelatin capsule of a lipid micro-emulsion formulation shows an approximate clearance of 22.5 L/h.

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.

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