CYCLOSPORINE

Pronounciation

• (sye-kloh-SPOR-een)

Trade Name(s)

• Sandimmune

• Immunosuppressant

Pretreatment:

Baseline studies may be indicated; see Monitor.

Cyclosporine:

5 to 6 mg/kg of body weight as a single dose 4 to 12 hours before transplantation. Repeat once each day until oral dosage form can be tolerated. Individualized adjustment is imperative and may be required on a daily basis. Administered at one-third of the oral dose in patients temporarily unable to take oral cyclosporine. Administered in conjunction with adrenal corticosteroids; different regimens used; see prescribing information.

Same as adult dose; however, higher doses may be required. See Maternal/Child.

Reduced dose may be required in impaired renal function and in patients with severe hepatic impairment.
■ Higher doses may be required in pediatric patients.
■ Lower-end doses may be indicated in the elderly. Consider impaired organ function and concomitant disease or other drug therapy.
■ Cyclosporine (Sandimmune) is not bioequivalent to Neoral (a brand of cyclosporine oral solution). Conversion from Neoral dosing to Sandimmune may result in lower cyclosporine blood concentrations. Blood concentration monitoring is indicated to avoid potential underdosing.
■ See Monitor and Drug/Lab Interactions.

Each 50 mg should be diluted immediately before use with 20 to 100 mL of NS or D5W and given as an infusion. May leach phthalate from polyvinylchloride containers; use diluents in glass infusion bottles. Dilute immediately before use and discard unused portion.

Filters:

Filtered through a 0.45-micron polypropylene filter during manufacturing. Has a high ethanol content, which the filter must accommodate. A large-bore needle filter may be used when withdrawing cyclosporine from an ampule. Adsorption should be negligible, but if there is concern, draw diluent through the same filter. In-line filtering is acceptable. Manufacturer indicates that cyclosporine molecules are small enough to pass through an in-line filter as small as 0.22 microns. Loss of potency is not expected. Another source used 0.22- and 0.45-micron filters and indicates an initial loss of potency that recovered to full concentration.

Storage:

Before use, store ampules at CRT. Protect from light. Discard diluted solution after 24 hours.

Leaches out plasticizers, including DEHP from PVC infusion bags and IV tubing; use of non-PVC containers and IV tubing recommended.

Other sources suggest a few specific compatibilities dependent on concentration and manufacturer; consult a pharmacist.

A single dose properly diluted as a slow IV infusion equally distributed over 2 to 6 hours.

A potent immunosuppressive agent. Interferes with IL-2 production and blocks T-cell proliferative signals during early T-cell activation. Prolongs survival of kidney, liver, and heart allogeneic transplants in the human. Measured by specific or nonspecific assays. Extensively metabolized by the cytochrome P₄₅₀ hepatic enzyme system. Half-life is 19 hours (range 10 to 27 hours). Primarily excreted in bile and to a small extent in urine. Crosses the placental barrier. Secreted in breast milk.

Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants in conjunction with adrenocortical steroids.
■ Treatment of chronic rejection in patients previously treated with other immunosuppressive agents. Reserve parenteral formulation for when oral administration not feasible.

Unlabeled uses:

Decrease frequency of pancreatic or corneal allograft rejection.
■ Prevention of acute graft-versus-host disease.
■ Crohn’s disease.

Hypersensitivity to cyclosporine or to Cremophor EL (polyoxyethylated castor oil).

Anaphylactic reactions have been reported with the IV formulation. These reactions may be related to the IV vehicle Cremophor EL; patients who experienced these reactions have subsequently been treated with the oral formulation of cyclosporine without incident. Because of the risk of anaphylaxis, IV cyclosporine should be reserved for patients who are unable to take oral therapy.
■ Usually administered in the hospital by or under the direction of a physician experienced in immunosuppressive therapy and management of organ transplant patients.
■ Adequate laboratory and supportive medical resources must be available.
■ All formulations may be given concomitantly with adrenocortical steroids. Manufacturer has a Black Box Warning. Do not administer cyclosporine with any other immunosuppressive agent except adrenocortical steroids.
■ Can cause hepatotoxicity and nephrotoxicity; see Monitor. In impaired renal function, if rejection is severe, try other immunosuppressive therapy or allow rejection and removal of the kidney rather than increase dose of cyclosporine.
■ May cause lymphomas and other malignancies, particularly those of the skin. Increased risk of developing a malignancy appears to be related to the intensity and duration of immunosuppression. Some malignancies may be fatal.
■ Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine-containing regimens, are at increased risk for infections (viral, bacterial, fungal, protozoal). Both generalized and localized infections can occur. Opportunistic infections include polyomavirus infections (e.g., JC virus–associated progressive multifocal leukoencephalopathy [PML]; polyoma virus–associated nephropathy [PVAN], especially due to BK virus infection). Pre-existing infections may be aggravated. Latent infections may be reactivated. Fatal outcomes have been reported.
■ Encephalopathy has been reported, including posterior reversible encephalopathy syndrome (PRES). May manifest as impaired consciousness, convulsions, visual disturbances (including blindness), loss of motor function, movement disorders, and psychiatric disturbances. Predisposing factors may include hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood levels, and graft-versus-host disease. Patients receiving liver transplants may be more susceptible to encephalopathy than patients receiving kidney transplants. Reversal of encephalopathy has occurred after discontinuation or dose reduction of cyclosporine.
■ Convulsions have been reported, particularly in patients receiving concomitant therapy with high-dose methylprednisolone.
■ Significant hyperkalemia (sometimes associated with hyperchloremic acidosis) and hyperuricemia have been reported.
■ A syndrome of thrombocytopenia and microangiopathic hemolytic anemia that may result in graft failure has been reported.
■ Optic disc edema, including papilledema, with possible visual impairment secondary to benign intracranial hypertension has been reported.
■ See Drug/Lab Interactions.

Monitor:

Observe for S/S of an anaphylactic reaction (e.g., blood pressure changes; bronchospasm; dyspnea; edema of face, tongue, or throat; itching; rash; tachycardia; wheezing). Monitor continuously for the first 30 minutes of the infusion and frequently thereafter.
■ Can cause hepatotoxicity and nephrotoxicity. Monitor BUN, SCr, serum bilirubin, and liver enzymes frequently. Timing and amount of rise in BUN and creatinine and degree of nephrotoxicity or hepatotoxicity distinguish between need for dose reduction or symptoms of organ rejection.
■ May be difficult to distinguish between nephrotoxicity and rejection. Up to 20% of patients may have simultaneous nephrotoxicity and rejection. See package insert for a chart discussing differential diagnoses for each.
■ Monitor cyclosporine blood levels. Measured by specific or nonspecific assay. 24-hour specific trough values of 100 to 200 ng/mL of whole blood or 24-hour nonspecific trough values of 250 to 800 ng/mL of whole blood minimize side effects and rejection events. Nonspecific assays trough values are higher because they include metabolites. Plasma levels may range from ½ to ⅕ of whole blood levels. Consistent use of one assay is recommended. Confirm assay method to evaluate appropriately.
■ Observe constantly for signs of infection (fever, sore throat, tiredness) or unusual bleeding or bruising.
■ Prophylactic antibiotics may be indicated pending results of C/S.
■ Monitor for development of PVAN and BK virus–associated nephropathy (e.g., deteriorating renal function and renal graft loss). Dose reduction may be indicated.
■ Monitor for development of PML (e.g., apathy, ataxia, cognitive deficiencies, confusion, hemiparesis). If symptoms appear, consultation with a neurologist may be indicated.
■ Monitor BP. Hypertension is a common side effect. Initiation or modification of antihypertensive therapy may be indicated; do not use potassium-sparing diuretics (e.g., spironolactone [Aldactone]); may increase risk of hyperkalemia.
■ Monitor for S/S of encephalopathy and/or PRES.
■ See Precautions and Drug/Lab Interactions.

Patient Education:

Use effective birth control. Do not use oral contraceptives. See Appendix D.
■ Do not make any changes in formulation (e.g., IV, capsules, oral solution) without physician direction; products are not equivalent. May require dose adjustment.
■ Review side effects with a health care professional and report all side effects promptly.
■ Capable of multiple drug-drug interactions; obtain physician approval before adding or stopping medications.
■ Compliance with frequent laboratory tests is imperative.

Maternal/Child:

Category C: safety for use in pregnancy not established. Should not be used unless benefit to the mother justifies potential risk to the fetus. Use in men and women capable of conception not established. Reported outcomes of pregnancies in women who received cyclosporine are difficult to evaluate. It is not possible to separate the effects of cyclosporine from the effects of other medications, underlying maternal disorders, or other aspects of the transplantation process. Negative outcomes included prematurity, low birth weight, fetal loss, and various malformations.
■ Discontinue breast-feeding.
■ Safety for use in pediatric patients not established but has been used in patients as young as 6 months of age. Accidental parenteral overdose in premature neonates has caused serious symptoms of intoxication.

Elderly:

Dose selection should be cautious; see Dose Adjustments.
■ Differences in response compared to younger adults not identified.

Interactions are numerous and potentially life threatening. Review of drug profile by pharmacist imperative.
■ Risk of nephrotoxicity increased when given with other drugs that may potentiate renal dysfunction. Use extreme caution and monitor renal function closely. If impairment of renal function is significant, either reduce the dose of cyclosporine and/or the coadministered drug, or consider an alternative treatment. Manufacturer lists antibiotics (e.g., ciprofloxacin, gentamicin, tobramycin, sulfamethoxazole/trimethoprim, vancomycin), antifungals (e.g., amphotericin B, ketoconazole), anti-inflammatory drugs (e.g., azapropazone, colchicine, diclofenac, naproxen, sulindac), H₂ antagonists (e.g., cimetidine, famotidine), immunosuppressives (e.g., tacrolimus), antineoplastics, and fibric acid derivatives (e.g., fenofibrate). Other sources list acyclovir, foscarnet (Foscavir), selected quinolones, and numerous other nephrotoxic drugs.
■ Concurrent administration with colchicine may cause cyclosporine toxicity (e.g., GI, hepatic, renal, and neuromuscular toxicity). Cyclosporine may decrease the clearance and increase the toxic effects of colchicine (e.g., myopathy, neuropathy), especially in patients with renal impairment. With concurrent use, close clinical observation is required. Reduce colchicine dose or discontinue as indicated.
■ May increase diclofenac (Voltaren) serum levels with concomitant administration; initiate diclofenac dose at the lower end of the therapeutic range.
■ Cyclosporine is extensively metabolized by CYP3A4 and is a substrate of the multidrug efflux transporter P-glycoprotein. Drugs that inhibit or induce CYP3A4, P-glycoprotein transporter, or organic anion transporter proteins will result in an alteration of cyclosporine concentrations. Toxicity or allograft rejection may occur. Compounds that decrease cyclosporine absorption, such as orlistat, should be avoided.
■ Cyclosporine plasma levels may be increased with concurrent use of protease inhibitors (e.g., boceprevir, indinavir, nelfinavir, ritonavir, saquinavir, telaprevir), which are metabolized by cytochrome P₄₅₀ 3A; use caution.
■ Drugs that inhibit the cytochrome P₄₅₀ system may decrease the metabolism of cyclosporine and increase its serum concentrations. Manufacturer lists allopurinol, amiodarone, antibiotics (e.g., azithromycin, clarithromycin, erythromycin, quinupristin/dalfopristin), antifungals (e.g., fluconazole, voriconazole), bromocriptine, calcium channel blockers, danazol, glucocorticoids, imatinib, metoclopramide, nefazodone, and oral contraceptives. Monitor blood levels with concurrent use to avoid cyclosporine toxicity.
■ Drugs that decrease cyclosporine concentrations should be avoided. Manufacturer lists antibiotics, anticonvulsants, bosentan, octreotide, orlistat, terbinafine, St. John’s wort, and sulfinpyrazone. Other sources list sulfamethoxazole/trimethoprim; monitor levels and adjust cyclosporine dose as indicated to avoid transplant rejection.
■ Rifabutin (Mycobutin) may increase metabolism of cyclosporine; use care with concomitant use.
■ Cyclosporine inhibits CYP3A4 and the multidrug efflux transporter P-glycoprotein and may increase plasma concentrations of co-medications that are substrates of CYP3A4, P-glycoprotein, or organic anion transporter proteins. Cyclosporine reduces clearance and may increase blood levels of ambrisentan, bosentan, dabigatran, digoxin, etoposide, methotrexate, NSAIDs, prednisolone, repaglinide, sirolimus, and other drugs. May decrease the volume distribution of digoxin and cause toxicity rather quickly. With concurrent use, monitor digoxin levels, reduce digoxin dose, or discontinue as indicated.
■ Concomitant use with NSAIDs, particularly in dehydrated patients, may potentiate renal dysfunction.
■ Avoid concurrent use with bosentan.
■ When coadministering ambrisentan with cyclosporine, the ambrisentan dose should not be titrated to the recommended maximum daily dose.
■ Cyclosporine may decrease the clearance of HMG-CoA reductase inhibitors (statins). Cases of myotoxicity (including muscle pain and weakness, myositis, and rhabdomyolysis) have been reported with concomitant use. Dose reduction of statins is indicated. Statins may be temporarily withheld or discontinued in patients with S/S of myopathy or potential for renal injury, including renal failure, secondary to rhabdomyolysis.
■ Coadministration with aliskiren (Tekturna) is not recommended.
■ May decrease mycophenolate levels. Monitor levels closely when cyclosporine is added or removed from a drug regimen containing mycophenolate.
■ Concurrent use of cyclosporine with imipenem-cilastatin may increase CNS toxicity of both agents.
■ Potentiates nondepolarizing muscle relaxants; will prolong neuromuscular blockade.
■ Do not use potassium-sparing diuretics; may increase risk of hyperkalemia. Use caution when coadministered with other potassium-sparing drugs, potassium-containing drugs, and/or in patients on a potassium-rich diet. Hyperkalemia can occur.
■ May cause convulsions with high doses of methylprednisolone.
■ May be given in combination with steroids but has additive effects with other immunosuppressive agents; may increase risk of lymphoma.
■ Concurrent administration with sirolimus increases blood levels of sirolimus. To minimize the effect on blood levels, administer sirolimus 4 hours after cyclosporine dose.
■ Elevations in SCr have been reported with coadministration of sirolimus and cyclosporine. Effect is usually reversible with cyclosporine dose reduction.
■ Serum levels may increase with chloroquine (Aralen).
■ Avoid use in psoriasis patients receiving other immunosuppressive agents or radiation therapy, including PUVA and UVB. Immunosuppression may be excessive.
■ May increase the plasma concentrations of repaglinide, which increases the risk for hypoglycemia. Monitor blood glucose levels closely.
■ Concurrent use with nifedipine has caused gingival hyperplasia; avoid use in patients who develop gingival hyperplasia.
■ High doses of cyclosporine (e.g., IV doses of 16 mg/kg/day) may increase the exposure to anthracycline antibiotics in cancer patients.
■ Monitor serum creatinine when used with NSAIDs in rheumatoid arthritis patients.
■ Vaccinations may be less effective. Avoid use of live virus vaccines in patients receiving cyclosporine.
■ Grapefruit juice may affect certain enzymes of the P₄₅₀ enzyme system and should be avoided.

The most common side effects include gum hyperplasia, hirsutism, hypertension, renal dysfunction, and tremor. Other side effects include acne, convulsions, cramps, diarrhea, encephalopathy, glomerular capillary thrombosis, headache, hepatotoxicity, hyperkalemia, hyperuricemia, hypomagnesemia, infection, leukopenia, lymphoma, microangiopathic hemolytic anemia, nausea and vomiting, paresthesia, skin rash, and thrombocytopenia. Hypersensitivity reactions including anaphylaxis have occurred. Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred rarely.

Post-Marketing:

Headache, including migraine; hepatotoxicity and liver injury, including cholestasis, hepatitis, jaundice, and liver failure with serious and/or fatal outcomes; isolated cases of pain in the lower extremities; JC virus–associated PML, sometimes fatal; and PVAN, especially due to BK virus infection, resulting in graft loss.

Notify physician of all side effects. Most can be treated symptomatically. Drug may be decreased or discontinued or other immunosuppressive agents utilized. Consider reducing total immunosuppression in transplant patients who develop PML or PVAN; may place graft at risk. Discontinue infusion at the first sign of a severe hypersensitivity reaction. Treat hypersensitivity as indicated; may require oxygen, epinephrine, antihistamines (e.g., diphenhydramine), vasopressors, corticosteroids, albuterol, IV fluids, and/or ventilation equipment. Nephrotoxicity, hepatotoxicity, encephalopathy (including PRES), or hematopoietic depression may require temporary reduction of dosage or permanent withholding of treatment. Dialysis is not effective in overdose.