indication

For treatment of transplant rejection, rheumatoid arthritis, severe psoriasis

pharmacology

Used in immunosuppression for prophylactic treatment of organ transplants, cyclosporine exerts specific and reversible inhibition of immunocompetent lymphocytes in the G0-or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T1-helper cell is the main target, although the T1-suppressor cell may also be suppressed. Sandimmune (cyclosporine) also inhibits lymphokine production and release including interleukin-2.

mechanism of action

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.

toxicity

The oral LD₅₀ is 2329 mg/kg in mice, 1480 mg/kg in rats, and > 1000 mg/kg in rabbits. The I.V. LD₅₀ is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.

biotransformation

Hepatic, extensively metabolized.

absorption

The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients.

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.

route of elimination

Elimination is primarily biliary with only 6% of the dose excreted in the urine. Only 0.1% of the dose is excreted in the urine as unchanged drug.

drug interactions

Acetazolamide: Acetazolamide may increase the effect and toxicity of cyclosporine.

Allopurinol: Allopurinol increases the effect and toxicity of cyclosporine

Amiodarone: Amiodarone may increase the therapeutic and adverse effects of cyclosporine.

Amobarbital: The barbiturate, amobarbital, increases the effect of cyclosporine.

Amphotericin B: Monitor for nephrotoxicity

Amprenavir: The protease inhibitor, amprenavir, may increase the effect of cyclosporine.

Aprobarbital: The barbiturate, aprobarbital, increases the effect of cyclosporine.

Atazanavir: Atazanavir may increase the therapeutic and adverse effects of cyclosporine.

Atorvastatin: Possible myopathy and rhabdomyolysis

Azithromycin: The macrolide, azithromycin, may increase the effect of cyclosporine.

Bezafibrate: Cyclosporine may enhance the nephrotoxic effect of fibric acid derivatives like bezafibrate. Fibric acid derivatives may decrease the serum concentration of cyclosporine. Extra monitoring of renal function and cyclosporine concentrations will likely be required. Adjustment of cyclosporine dose may be necessary.

Bosentan: Cyclosporine may increase the effect and toxicity of bosentan.

Bupropion: Bupropion may decrease the therapeutic effect of cyclosporine.

Butabarbital: The barbiturate, butabarbital, increases the effect of cyclosporine.

Butalbital: The barbiturate, butalbital, increases the effect of cyclosporine.

Butethal: The barbiturate, butethal, increases the effect of cyclosporine.

Carbamazepine: Carbamazepine may decrease the therapeutic effect of cyclosporine.

Carvedilol: Carvedilol may increase the therapeutic and adverse effects of cyclosporine.

Caspofungin: Cyclosporine increases the effect and toxicity of caspofungin

Cerivastatin: Possible myopathy and rhabdomyolysis

Chloramphenicol: Chloramphenicol may increase the effect of cyclosporine.

Chloroquine: Chloroquine may increase the therapeutic and adverse effects of cyclosporine.

Cilastatin: Imipenem increases the effect and toxicity of cyclosporine

Ciprofloxacin: Ciprofloxacin may increase the effect and toxicity of cyclosporine.

Clarithromycin: The macrolide, clarithromycin, may increase the effect of cyclosporine.

Clindamycin: Clindamycin may decrease the therapeutic effect of cyclosporine.

Colchicine: Increased toxicity of both drugs

Danazol: The androgen, danazol, may increase the effect and toxicity of cyclosporine.

Diclofenac: Monitor for nephrotoxicity

Digoxin: Cyclosporine may increase the effect of digoxin.

Dihydroquinidine barbiturate: The barbiturate, dihydroquinidine barbiturate, increases the effect of cyclosporine.

Diltiazem: Diltiazem may increase the effect and toxicity of cyclosporine.

Efavirenz: Efavirenz decreases the levels of cyclosporine

Erythromycin: The macrolide, erythromycin, may increase the effect of cyclosporine.

Ethinyl Estradiol: The contraceptive increases the effect and toxicity of cyclosporine

Ethotoin: The hydantoin decreases the effect of cyclosporine

Etodolac: Monitor for nephrotoxicity

Etoposide: Cyclosporine may increase the therapeutic and adverse effects of etoposide.

Ezetimibe: Cyclosporine may increase the therapeutic and adverse effects of ezetimibe.

Fenoprofen: Monitor for nephrotoxicity

Fluconazole: Fluconazole may increase the therapeutic and adverse effects of the cyclosporine.

Fluoxetine: The antidepressant increases the effect and toxicity of cyclosporine

Flurbiprofen: Monitor for nephrotoxicity

Fluvastatin: Possible myopathy and rhabdomyolysis

Fosamprenavir: The protease inhibitor, fosamprenavir, may increase the effect of cyclosporine.

Foscarnet: Monitor for nephrotoxicity

Fosphenytoin: The hydantoin decreases the effect of cyclosporine

Glimepiride: The sulfonylurea, glimepiride, may increase the effect of cyclosporine.

Glipizide: The sulfonylurea, glipizide, may increase the effect of cyclosporine.

Glyburide: The sulfonylurea, glibenclamide, may increase the effect of cyclosporine.

Griseofulvin: Griseofulvin decreases the effect of cyclosporine

Heptabarbital: The barbiturate, heptabarbital, increases the effect of cyclosporine.

Hexobarbital: The barbiturate, hexobarbital, increases the effect of cyclosporine.

Ibuprofen: Monitor for nephrotoxicity

Imatinib: Imatinib increases the effect and toxicity of cyclosporine

Imipenem: Imipenem increases the effect and toxicity of cyclosporine

Indinavir: The protease inhibitor, indinavir, may increase the effect of cyclosporine.

Indomethacin: Monitor for nephrotoxicity

Itraconazole: Itraconazole may increase the effect of cyclosporine.

Josamycin: The macrolide, josamycin, may increase the effect of cyclosporine.

Ketoconazole: Ketoconazole may increase the effect of cyclosporine.

Ketoprofen: The NSAID, ketoprofen, may increase the serum concentration of cyclosporine. Ketoprofen may also increase the nephrotoxicity of cyclosporine.

Lovastatin: Possible myopathy and rhabdomyolysis

Meclofenamic acid: Monitor for nephrotoxicity

Mefenamic acid: Monitor for nephrotoxicity

Melphalan: Melphalan increases toxicity of cyclosporine

Mephenytoin: The hydantoin decreases the effect of cyclosporine

Mestranol: The contraceptive increases the effect and toxicity of cyclosporine

Methohexital: The barbiturate, methohexital, increases the effect of cyclosporine.

Methotrexate: Cyclosporine may increase the effect and toxicity of methotrexate.

Methylphenidate: Methylphenidate increases the effect and toxicity of cyclosporine

Methylphenobarbital: The barbiturate, methylphenobarbital, increases the effect of cyclosporine.

Metoclopramide: Metoclopramide increases serum levels of cyclosporine

Modafinil: Modafinil decreases the effect of cyclosporine

Muromonab: Muromonab increases the levels of cyclosporine

Nabumetone: Monitor for nephrotoxicity

Nafcillin: Nafcillin alters serum levels of cyclosporine

Naproxen: Monitor for nephrotoxicity

Nefazodone: The antidepressant increases the effect and toxicity of cyclosporine

Nelfinavir: The protease inhibitor, nelfinavir, may increase the effect of cyclosporine.

Nicardipine: Nicardipine increases the effect and toxicity of cyclosporine

Nifedipine: Increased risk of gingivitis

Norfloxacin: Norfloxacin may increase the effect and toxicity of cyclosporine.

Octreotide: Octreotide decreases the effect of cyclosporine

Omeprazole: Omeprazole increases the effect and toxicity of cyclosporine

Orlistat: Orlistat decreases the effect of cyclosporine

Oxaprozin: Monitor for nephrotoxicity

Oxcarbazepine: Oxcarbazepine decreases the effect of cyclosporine

Pentobarbital: The barbiturate, pentobarbital, increases the effect of cyclosporine.

Phenobarbital: The barbiturate, phenobarbital, may decrease the therapeutic effect of cyclosporine by increasing its metabolism.

Phenytoin: The hydantoin decreases the effect of cyclosporine

Piroxicam: Monitor for nephrotoxicity

Posaconazole: Increased level of cyclosporine

Pravastatin: Possible myopathy and rhabdomyolysis

Primidone: The barbiturate, primidone, increases the effect of cyclosporine.

Probucol: Probucol decreases the effect of cyclosporine

Propafenone: Propafenone increases the effect and toxicity of cyclosporine

Pyrazinamide: Pyrazinamide decreases the effect of cyclosporine

Quinidine barbiturate: The barbiturate, quinidine barbiturate, increases the effect of cyclosporine.

Quinupristin: Synercid increases the effect of cyclosporine

Repaglinide: Cyclosporine may increase the therapeutic and adverse effects of repaglinide.

Rifabutin: The rifamycin decreases the effect of cyclosporine

Rifampin: The rifamycin decreases the effect of cyclosporine

Ritonavir: The protease inhibitor, ritonavir, may increase the effect of cyclosporine.

Rosuvastatin: Cyclosporine may increase the serum concentration of rosuvastatin. Limit rosuvastatin dosing to 5 mg/day and monitor for changes in the therapeutic and adverse effects of rosuvastatin if cyclosporine is initiated, discontinued or dose changed.

Roxithromycin: The macrolide, roxithromycin, may increase the effect of cyclosporine.

Saquinavir: The protease inhibitor, saquinavir, may increase the effect of cyclosporine.

Secobarbital: The barbiturate, secobarbital, increases the effect of cyclosporine.

Sevelamer: Sevelamer decreases the effect of cyclosporine

Sibutramine: Sibutramine increases the effect and toxicity of cyclosporine

Simvastatin: Possible myopathy and rhabdomyolysis

Sirolimus: Increases the effect and toxicity of sirolimus

St. John's Wort: St. John's Wort decreases the effect of cyclosporine

Sulfadiazine: The sulfonamide decreases the effect of cyclosporine

Sulfamethazine: The sulfonamide decreases the effect of cyclosporine

Sulfamethoxazole: The sulfonamide decreases the effect of cyclosporine

Sulfasalazine: The sulfonamide decreases the effect of cyclosporine

Sulfinpyrazone: Sulfinpyrazone decreases the effect of cyclosporine

Sulindac: The NSAID, sulindac, may increase the nephrotoxic effect of cyclosporine. Sulindac may increase the serum concentration of cyclosporine. Consider alternate therapy or monitor for increased cyclosporine levels and nephrotoxicity during concomitant therapy.

Tacrolimus: Additive renal impairment may occur during concomitant therapy with cyclosporine. Combination therapy should be avoided.

Talbutal: The sulfonamide decreases the effect of cyclosporine

Tamsulosin: Cyclosporine, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Cyclosporine is initiated, discontinued, or dose changed.

Telithromycin: Telithromycin may reduce clearance of cyclosporine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of cyclosporine if telithromycin is initiated, discontinued or dose changed.

Tenoxicam: Monitor for nephrotoxicity

Terbinafine: Terbinafine may decrease the plasma concentration and therapeutic effect of cyclosporine.

Testolactone: The androgen, Testolactone, may increase the hepatotoxicity of Cyclosporine. Testolatone may also elevate serum concentrations of Cyclosporine. Consider alternate therapy or monitor for signs of renal and hepatic toxicity.

Testosterone: The androgen, Testosterone, may increase the hepatotoxicity of Cyclosporine. Testosterone may also elevate serum concentrations of Cyclosporine. Consider alternate therapy or monitor for signs of renal and hepatic toxicity.

Testosterone Propionate: The androgen, Testosterone, may increase the hepatotoxicity of Cyclosporine. Testosterone may also elevate serum concentrations of Cyclosporine. Consider alternate therapy or monitor for signs of renal and hepatic toxicity.

Thiopental: Thiopental may increase the metabolism and clearance of Cyclosporine. Monitor for changes in the therapeutic/adverse effects of Cyclosporine if Thiopental is initiated, discontinued or dose changed.

Tiaprofenic acid: Tiaprofenic acid may increase the nephrotoxicity and/or the serum concentration of cyclosporine. Consider altnerate therapy or monitor for increased cyclosporine concentrations and nephrotoxicity during concomitant therapy.

Ticlopidine: Ticlopidine decreases the effect of cyclosporine

Tipranavir: Tipranavir may affect the efficacy/toxicity of Cyclosporine.

Tobramycin: Increased risk of nephrotoxicity

Tolmetin: Tolmetin may increase the serum concentration of cyclosporine and/or increase the nephrotoxicity of cyclosporine. Consider alternate therapy or monitor for increased cyclosporine serum concentration and nephrotoxicity during concomitant therapy.

Tolterodine: Cyclosporine may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Topotecan: The p-glycoprotein inhibitor, Cyclosporine, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Tramadol: Cyclosporine may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Trandolapril: The ACE inhibitor, Trandolapril, may increase the nephrotoxicity of Cyclosporine.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Trazodone: The CYP3A4 inhibitor, Cyclosporine, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Cyclosporine is initiated, discontinued or dose changed.

Troglitazone: Troglitazone decreases the effect of the immunosuppressant

Troleandomycin: The macrolide, troleandomycin, may increase the effect of cyclosporine.

Ursodeoxycholic acid: Ursodiol increases the levels of cyclosporine

Verapamil: Verapamil may increase the serum concentration of cyclosporine by inhibiting CYP3A4-mediated metabolism of cyclosporine. Monitor for changes in the therapeutic/adverse effects of cyclosporine if verapamil is initiated, discontinued or dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of cyclosporine by decreasing its metabolism. Consider reducing the dose of cyclosporine. Monitor cyclosporine serum concentrations and therapeutic and toxic effects if initiating, discontinuing or adjusting voriconazole therapy.