Cyclosporin A Property

Melting point:

148-151°C

Boiling point:

838.63°C (rough estimate)

alpha 

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

Density 

0.9913 (rough estimate)

refractive index 

1.6500 (estimate)

Flash point:

87℃

storage temp. 

-20°C

solubility 

ethanol: 30 mg/mL

form 

solid

pka

13.32±0.70(Predicted)

color 

white

Water Solubility 

Soluble in dimethyl sulfoxide and ethanol. Insoluble in water.

Merck 

14,2752

BRN 

3647785

Stability:

Stable for 3 years as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.

InChIKey

PMATZTZNYRCHOR-CGLBZJNRSA-N

CAS DataBase Reference

59865-13-3(CAS DataBase Reference)

IARC

1 (Vol. 50, 100A) 2012

EPA Substance Registry System

Cyclosporin A (59865-13-3)

Safety

Hazard Codes 

T,Xn,F

Risk Statements 

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

Safety Statements 

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

RIDADR 

UN 1648 3 / PGII

WGK Germany 

3

RTECS 

GZ4120000

HS Code 

29419090

Hazardous Substances Data

59865-13-3(Hazardous Substances Data)

Toxicity

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

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Danger

Hazard statements

H302Harmful if swallowed

H350May cause cancer

Precautionary statements

P201Obtain special instructions before use.

P202Do not handle until all safety precautions have been read and understood.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P270Do not eat, drink or smoke when using this product.

P301+P312IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.

P308+P313IF exposed or concerned: Get medical advice/attention.

Cyclosporin A Chemical Properties,Usage,Production

Immunosuppressants

Cyclosporin A is a lipophilic cyclic peptide compounds separated by certain Hyphomycetes fungi, such as Cylindrocarpon lucidum and Tolypocladium inflatumculture medium. In 1980s, as an immunosuppressant, it has been widely used in the world, is now used for a variety of tissues and organ transplant to prevent rejection reaction and to treat autoimmune diseases.
Cyclosporin A is a strong immunosuppressant, inhibits the onset of the reaction in cell media, reversibly inhibits T cell proliferation, does not inhibit the generation of blood cells, does not affect the function of the phagocyte. As compared with other inhibitors, fewer advantages are induce or aggravate infection, mainly used in clinical kidney, liver, heart, lung, bone marrow transplant anti-rejection, can be combined with adrenal corticosteroids, but not in combination with other immunosuppressive agents. Also used in certain autoimmune diseases (such as systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, autoimmune hemolytic anemia). Try to uveitis, severe aplastic anemia, refractory idiopathic thrombocytopenic purpura, psoriasis, etc.

Pharmacological effects

Cyclosporin A can reversibly selectively alter T-lymphocyte function, prevent transcription of lymphokine gene, interfere transfer of original information, inhibit the release of interleukin-2, interferon and other immune factors, affect humoral immunity and immune cells, inhibit killing viability of NK cell; inhibit differentiation and proliferation of lymphocyte in the antigen or mitogen stimulation. But no activity on bone marrow, very small effect on B cells, at therapeutic doses no significant inhibiting effect on granulocyte survival. Oral absorption is slow and incomplete, only 4% to 60%, an average is 30% of the administered dose; relative bioavailability is 20% to 50%. After 2~8h of oral administration reach its peak, with an average of 3.5h. Significant individual differences, such as the relative bioavailability of renal transplant patients is 5% to 89%, liver transplant patients is 8% to 60%. This product is fat-soluble drug, meals and eating food can increase the absorption of fat. Bile deficiency, stagnation, slow gastric emptying, increased gastric peristalsis, pancreatic dysfunction and steatorrhea, all affect absorption of the product.

Pharmacokinetics

Oral absorption is irregular and big differences in different individual, bioavailability is 30%, but can be increased with the extended duration of treatment and the increased dose. After liver transplantation, patients with liver disease or disorder of the gastrointestinal absorption may be reduced . Binding rate this product with plasma proteins is up to about 90%, mainly in combination with lipoproteins. Oral peak time is 3 to 4 hours, whole blood concentration is 2 to 9 times of plasma, adult plasma T1/2 is 19 (10-27) hours, while the child is only 7 (7 to 19) hours. This product is metabolized in the liver, by biliary excretion through feces, only 6% by renal excretion, of which about 0.1% is excreted in the primary form.
The above information is edited by the Chemicalbook of Liu Yujie.

Indications

For prevention of a variety of tissue and organ transplant rejection and treatment of some autoimmune diseases, also used in kidney disease, aplastic anemia, refractory ulcerative colitis. In dermatology, for stubborn and intractable skin diseases, the best effect is severe psoriasis (including vulgaris, pustular, erythrodermic and joint disease); good efficacy on skin disorders including Behcet disease, gangrenous pyoderma, lichen planus, acquired epidermolysis bullosa psychosis; moderate efficacy on disease including alopecia, atopic dermatitis, chronic actinic dermatitis, light class of reticulocyte cell histiocytosis, adult linear IgA bullous dermatitis, pemphigus, bullous pemphigoid (the latter two illness should be in combination with corticosteroids). In addition, Cyclosporine A has effect on systemic lupus erythematosus, dermatomyositis, systemic sclerosis, AIDS, ichthyosis, cutaneous T-cell lymphoma, pityriasis rubra pilaris, generalized missed acrodermatitis, palmoplantar pus blister disease, male pattern baldness, vitiligo, progressive necrotizing xanthogranulomatous, generalized granuloma annulare, lichen myxedema, papular mucin calm disease, hyperthyroidism.

Drug interactions

1, In addition to corticosteroids, this product should be avoided in combination with any other immunosuppressive agents.
2, The inactivation of product is mainly in the liver metabolic, any drugs which can affect the liver enzyme activities can affect the metabolism of the product, such as erythromycin, josamycin, doxycycline, ketoconazole, H2 receptor antagonists , calcium antagonists, androgens, oral contraceptives affect activity of cytochrome P-450 liver cell, increase the risk of toxicity of this product.
3, Carbamazepine, phenytoin, phenobarbital, isoniazid, rifampin, et al. can make the plasma concentration of this product decrease.
4, Aminoglycoside antibiotic, trimethoprim-sulfamethoxazole, TMP, amphotericin B, cephalosporins, mechlorethamine, nonsteroidal anti-inflammatory drug, mannitol, furosemide, et al increase nephrotoxicity of cyclosporine .
5, Calcium and increased calcium are disabled when using this product, and cannot be vaccinated.
6, Long-term in combination with glucocorticoid can trigger diabetes, hypertension, ulcer disease and osteoporosis, and can increase the toxicity of this product.
7, Before used Cyclosporin A, other immunosuppressive agents are used, patients have overall decreased immunity and are easy to be infected.

Side effects

1, Kidney toxicity: accounted for about 13%, may have glomerular thrombosis, tubular obstruction, mitochondrial swelling, proteinuria, tubular urine; occasionally hyperuricemia, hyperkalemia, elevated serum creatinine, blood urea nitrogen rise, little or no urine.
2, Liver toxicity: hypoproteinemia, hyperbilirubinemia, serum alkaline phosphatase and lactate dehydrogenase elevated, when the serum concentration of the drug is greater than 200ng/ml most likely to occur, especially in the original hepatitis or liver dysfunction.
3, Nervous system: usually presents exercise-induced spinal cord syndrome, cerebellar ataxia, mental confusion, tremors, abnormal feeling, etc.
4, Gastrointestinal reactions: common anorexia, nausea, and vomiting. Other reactive hypertension, hirsutism. When administered intravenously, rare serious allergic reactions such as chest facial flushing, breathing difficulties, asthma, heart palpitations; once presents the above symptoms, should be discontinued immediately and anti-shock first aid.

Chemical properties

From-15 ℃ of acetone to obtain white needle crystallization, melting point 148~151 ℃, [α] D20-244 ° (C = 0.6, chloroform). Soluble in methanol, ethanol, acetone, ether or chloroform, slightly soluble in water and saturated hydrocarbons. Acute toxicity LD50 mouse, rat, rabbit (mg/kg): 107, 25, > 10 intravenous injection; 2329,1480,> 1000 oral.

Production methods

Used Tolypocladium inflatum Gams as production strains. 50L seed medium is added into 75 L tank, inoculated with 5 × 109 spores, Ph = 5.4-4.3, cultured for 72 h, to obtain first order seed liquid. 500L fermentation medium is added into 750 L fermentation tank, inoculated with above first order seed liquid, cultured for 6 days to give second order seed liquid. 3000L fermentation medium is added into 4500L fermentation tank, fermentation for 12 days to give fermented cyclosporine toxicity. An equal volume of ethyl acetate is added into the fermentation broth, organic layer was separated, evaporated under reduced pressure to give the crude product. Melting process, can obtain Cyclosporin A and Cyclosporin C component, wherein Cyclosporin A production is about 150~200 mg/L, Cyclosporin C is about 50~100 mg/L.

Description

Cyclosporine A is a powerful immunosuppressive drug intended for preventing rejection of kidney, heart, and lung transplants. A new era in the development of immunopharmacology began with the discovery of cyclosporines. Cyclosporines are produced by mycelial mushrooms Tolypocladium inflatum, Tricoderma polysporum, and Cylindrocarpon lucidum, which are found in the ground.
Cyclosporine A is the first drug to affect a specific line of protecting cells of the body. Unlike usual cytotoxics, it suppresses T-cells and acts on all cell lines simultaneously. Cyclosporine A significantly eases the ‘reception’ of transplants, and increases the possibility of treating autoimmune system diseases.

Chemical Properties

White or almost white powder

Chemical Properties

White crystalline solid or powder.

Originator

Sandimmune,Sandoz,US,1983

Uses

An immunosuppressant that has revolutionized organ transplantation through its use in the prevention of graft rejection. A group of nonpolar cyclic oligopeptides with immunosupppressant activity.

Uses

prothrombogenic agent

Uses

Cyclosporin A is a hydrophobic cyclic peptide isolated from several fungal species including Cylindrocarpon, Fusarium, Trichoderma and Tolypocladium. Cyclosporin A inhibits T-cell activation and has been marketed since 1983 as an immunosuppressant in post-allogeneic organ transplant. Cyclosporin A acts by binding to the protein, cyclophilin (immunophilin), in T-lymphocytes causing inhibition of calcineurin (protein phosphatase 2B). Cyclosporin A reduces transcription of interleukin 2, and inhibits lymphokine production, interleukin release and NO synthesis induced by interleukin 1α, lipopolysaccharides and TNFα.

Definition

ChEBI: A cyclic nonribosomal peptide of eleven amino acids; an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient's immune system, and therefore the risk of organ rejection. Also causes reversible inhibiti n of immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle.

Indications

Manufacturing Process

10 liters of a nutrient solution (of which each liter contains 30 g of sucrose, 10 g of corn steep, 3 g of NaNO3, 1 g of K2HPO4, 0.5 g of MgSO4·7H2O, 0.5 g of KCl and 0.01 g of FeSO4·7H2O) are inoculated with 100 cc of a conidia and mycelium suspension of the strain NRRL 5760, and incubation is effected in 700 cc penicillin flasks at 27°C for 11 days.
The mycelium, which has been separated from the culture liquid, is extracted in a Turrax apparatus by crushing and stirring with 3.5 liters of 90% methanol, and the crushed mycelium, which is separated from the solvent by filtering with suction, is again treated twice in the same manner with 90% methanol. The combined filtrates are concentrated by evaporation in a vacuum at a bath temperature of 40°C to such an extent that the vapor mainly consists of water alone. The resulting mixture is extracted six times with the same volume of ethylene chloride by shaking, whereupon the combined ethylene chloride solutions are purified by extraction with water and are concentrated by evaporation in a vacuum at a bath temperature of 40°C. The resulting residue is chromatographed on 250 g of silica gel (silica gel 60 Merck, grain size 0.063-0.200 mm), using chloroform containing 2% of methanol as eluant, and is collected in 200 cc fractions. The fractions which are antibiotically active against Aspergillus niger in the plate diffusion test are combined, evaporated to dryness as described above, and after dissolving in methanol are chromatographed on 110 g of Sephadex LH20 with the same solvent, whereupon those 20 cc fractions showing an antibiotic effect against Aspergillus niger in the test indicated above, are combined. A test in the thin layer chromatogram, e.g., with silica gel on Polygram foils and hexane/acetone (1:1) as eluant, indicates that the residue of the methanol solution evaporated as described above mainly consists of the two new antibiotics S 7481/F-1 and S 7481/F-2. These are separated and simultaneously purified by a further chromatography of the mixture thereof, using a 1,000-fold amount of silica gel on the above indicated quality and chloroform contains 2% of methanol. A testing of the eluate fractions having a volume in milliliters which is half as large as the weight of the silica gel in grams, in the thin layer chromatogram, indicates that the antibiotic S 7481/F- 1 appears first in the eluate, followed by a mixture of the two antibiotics and finally by homogeneous S748l/F-2.
Further amounts of the two antibiotics may be obtained from the mixture by repeating chromatography under the same conditions.

brand name

Gengraf (Abbott); Neoral (Novartis); Restasis (Allergan); Sandimmune (Novartis) [Names previously used: Cyclosporin A; Cyclosporin.].

Therapeutic Function

Immunosuppressive

General Description

White prismatic needles (from acetone) or white powder.

Air & Water Reactions

Slightly water soluble .

Reactivity Profile

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).

Health Hazard

SYMPTOMS: Symptoms of exposure to Cyclosporin A 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.

Fire Hazard

Flash point data for Cyclosporin A are not available; however, Cyclosporin A is probably combustible.

Biochem/physiol Actions

Cyclosporin A is a non-polar cyclic oligopeptide produced by the fungus Tolypocladium inflatum. It is a potent immunosuppressive agent, affecting primarily T-lymphocytes. It has been shown to inhibit the functioning of several nuclear proteins involved in T-cell activation at the level of mRNA transcription. It forms a complex with its intracellular receptor cyclophilin, which can then bind to calcineurin, a Ca2+- and calmodulin-dependent protein phosphatase, inhibiting its enzymatic activity. CsA was found to suppress the replication of hepatitis C virus genome in cultured hepatocytes. At concentrations >10 nM, CsA protected isolated hepatocytes against the action of phalloidin. CsA can inhibit IL2 production resulting from T cell activation via Calcineurin inhibition.An extensive list of references has been reported, including a comprehensive review of analytical properties.

Pharmacology

Cyclosporine has no direct effect on keratinocytes and is not a mitotic inhibitor. Cyclosporine inhibits cytokine release, which results in a decreased recruitment of APCs into the epidermis and decreases immunoreactivity of lesions. Potential long-term side effects preclude cyclosporine’s use in all but very severe and recalcitrant psoriasis. Cyclosporine can be combined with lowdose methotrexate.

Clinical Use

Immunosuppressant:
Prophylaxis of solid organ transplant rejection

Nephrotic syndrome

Atopic dermatitis

Psoriasis

Rheumatoid arthritis

Ulcerative colitis

Side effects

Cyclosporine’s main side effects, even at low doses, are hypertension and nephrotoxicity. Age, baseline blood pressure, and baseline creatinine levels are predictors of higher risks of side effects. Glomerular filtration rate (GFR) is a more sensitive test than creatinine for evaluating renal function, and a baseline is recommended in any high-risk patient. Longterm treatment with CSA may induce interstitial fibrosis and glomerular sclerosis, with more pronounced changes directly associated with duration of therapy. It should be administered only by dermatologists experienced in its use.

Safety Profile

Confirmed carcinogen producing Hodghn's dlsease. Experimental reproductive effects. Poison by intraperitoneal and intravenous routes. Moderately toxic by ingestion. Human systemic effects by ingestion: increased body temperature, cyanosis. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Cyclosporine A, [R-[R* ,R* -(E)]]-cyclo-(L-alanyl-D-alanyl-N-methyl-Lleucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6- octenoyl-L-α-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine) (31.2.2), is extracted from a cultural liquid of products of the vital activity of the mushroom Tolypocladium inflatum [14–17], and which is also proposed to obtain synthetically.

Potential Exposure

Cyclosporin A is a fungal metabolite; an amide immunosuppressant drug used in various surgeries.

Drug interactions

Potentially hazardous interactions with other drugs
Increased risk of hyperkalaemia with ACE inhibitors, angiotensin-II antagonists, potassiumsparing diuretics, potassium salts.
Increased risk of nephrotoxicity with aminoglycosides, amphotericin, co-trimoxazole, disopyramide, foscarnet, melphalan, NSAIDs, polymyxins, quinolones, sulphonamides, thiazide diuretics, trimethoprim and vancomycin.
Increased ciclosporin levels with acetazolamide, aciclovir, amiodarone, atazanavir, boceprevir, carvedilol, chloramphenicol, chloroquine, cimetidine, danazol, diltiazem, doxycycline, famotidine, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, glibenclamide, glipizide, grapefruit juice, hydroxychloroquine, imatinib, indinavir, itraconazole, ketoconazole, lercanidipine (concentration of both drugs increased - avoid), macrolides, micafungin, miconazole, high-dose methylprednisolone, metoclopramide, metronidazole, muromonabCD3, nicardipine, posaconazole, progestogens, propafenone, ritonavir, saquinavir and telaprevir (concentration of both drugs increased), tacrolimus, verapamil and voriconazole.
Decreased ciclosporin levels with barbiturates, bupropion, carbamazepine, efavirenz, fosphenytoin, griseofulvin, lanreotide, modafinil, octreotide, pasireotide, phenytoin, primidone, quinine, red wine, rifampicin, St John’s wort, sulfadiazine, IV sulfadimidine, sulfasalazine, sulfinpyrazone,terbinafine, ticlopidine and IV trimethoprim and possibly by oxcarbazepine.
Aliskiren: concentration of aliskiren increased - avoid.
Ambrisentan: concentration of ambrisentan increased.
Antibacterials: increased risk of myopathy with daptomycin - try to avoid concomitant use.
Anticoagulants: concentration of dabigatran and edoxaban increased - avoid with dabigatran and reduce dose of edoxaban.
Antidiabetics: may increase repaglinide concentration, risk of hypoglycaemia.
Antimuscarinics: avoid with darifenacin.
Antivirals: avoid with simeprevir, increased simeprevir concentration; when starting coadministration with dasubavir and ombitasvir/ paritaprevir/ritonavir, give one fifth of the total daily dose of ciclosporin once daily. Monitor ciclosporin levels and adjust dose and/or dosing frequency as needed.
Basiliximab: may alter ciclosporin levels.
Bosentan: co-administration of ciclosporin and bosentan is contraindicated. When ciclosporin and bosentan are co-administered, initial trough concentrations of bosentan are 30 times higher than normal. At steady state, trough levels are 3-4 times higher than normal. Blood concentrations of ciclosporin decreased by 50%.
Calcium-channel blockers: increased nifedipine concentration and toxicity; amlodipine may increase ciclosporin concentration by up to 40%.
Cardiac glycosides: increased digoxin concentration and toxicity.
Caspofungin: caspofungin concentration increased - monitor LFTs.
Colchicine: risk of myopathy or rhabdomyolysis; also increased blood-ciclosporin concentrations and nephrotoxicity - avoid.
Cytotoxics: increased risk of neurotoxicity with doxorubicin; concentration of epirubicin, everolimus and idarubicin increased; reduced excretion of mitoxantrone; increased toxicity with methotrexate; seizures have been reported in bone marrow transplant patients taking busulfan and cyclophosphamide; use crizotinib with caution; concentration of etoposide possibly increased (increased risk of toxicity); possible interaction with docetaxol.
Eltrombopag: exposure reduced by ciclosporin.
Fidaxomicin: avoid concomitant use.
Lenalidomide: concentration of lenalidomide increased.
Lipid-lowering agents: absorption reduced by colesevelam, increased risk of myopathy with statins (avoid with simvastatin, max dose of atorvastatin should be 10 mg1 ); avoid with rosuvastatin; increased risk of nephrotoxicity with fenofibrate; bezafibrate may increase creatinine and reduce ciclosporin levels; concentration of both drugs may be increased with ezetimibe.
Mycophenolate mofetil: some studies show that ciclosporin decreases plasma MPA AUC levels - no dose change required.
NSAIDs: diclofenac concentration increased - reduce diclofenac dose.
Omeprazole: may alter ciclosporin concentration.
Orlistat: absorption of ciclosporin possibly reduced.
Prednisolone: increased prednisolone concentration.
Rifaximin: concentration of rifaximin increased.
Sirolimus: increased absorption of sirolimus - give sirolimus 4 hours after ciclosporin; sirolimus concentration increased; long term concomitant administration may be associated with deterioration in renal function.
Tacrolimus: increased ciclosporin concentration and toxicity - avoid.
Ursodeoxycholic acid: unpredictably increased absorption and raised ciclosporin levels in some patients.

Carcinogenicity

Cyclosporin A is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.

Metabolism

Ciclosporin is widely distributed throughout the body. Distribution in the blood is concentration-dependent, with between 41-58% in erythrocytes and 10-20% in leucocytes; the remainder is found in plasma, about 90% protein-bound, mostly to lipoprotein.
Clearance from the blood is biphasic. Ciclosporin is extensively metabolised in the liver and mainly excreted in faeces via the bile. About 6% of a dose is reported to be excreted in the urine, less than 0.1% unchanged.

storage

-20°C (desiccate)

Shipping

UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Incompatibilities

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 such as hydrideds and active metals. 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 such as phosphorus pent- oxide or thionyl chloride generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

Waste Disposal

t is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consider- ation applicable DEA, EPA, and FDA regulations. If possi- ble return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged, and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

References

1) Liu et al. (1993), FK506 and cyclosporin: molecular probes for studying intracellular signal transduction; Trends Pharmacol. Sci., 18 334