Brand names: Gengraf, Neoral, SandIMMUNE
Drug class: Calcineurin Inhibitors, Miscellaneous

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Immunosuppressive agent and disease-modifying antirheumatic drug (DMARD); cyclic polypeptide.

Uses for Cyclosporine

Renal, Hepatic, and Cardiac Allotransplantation

Prevention of allograft rejection in kidney, liver, or heart transplant patients.

Treatment of chronic allograft rejection in patients previously treated with other immunosuppressive agents (e.g., azathioprine).

Manufacturers state that corticosteroid therapy should be used concomitantly with IV cyclosporine and conventional (nonmodified) oral formulations (Sandimmune) and be administered concomitantly, at least initially, with modified oral formulations (Gengraf or Neoral). Alternatively, some clinicians believe that routine concomitant use of corticosteroids during cyclosporine therapy is not necessary and that their use should be reserved for acute periods of allograft rejection.

Bone Marrow Allotransplantation

Prevention of acute graft-vs-host disease following bone marrow transplantation^{† [off-label]}.

Has been used for the treatment of moderate to severe, acute graft-vs-host disease^{† [off-label]} following bone marrow transplantation.

Rheumatoid Arthritis

Management of the active stage of severe rheumatoid arthritis in selected adults who have an inadequate response to methotrexate; may be used in combination with methotrexate in those who do not respond adequately to methotrexate monotherapy.

Treatment of rheumatoid arthritis in adults who had an insufficient response to or did not tolerate NSAIAs^{† [off-label]} and other DMARDs^{† [off-label]} .

Psoriasis

Treatment of immunocompetent adults with severe (i.e., extensive and/or disabling), recalcitrant plaque psoriasis that is not adequately responsive to ≥1 systemic therapy (e.g., retinoids, methotrexate, PUVA) or in patients for whom other systemic therapy is contraindicated or cannot be tolerated.

Crohn’s Disease

Has been used with some success in the management of refractory inflammatory, fistulizing, and chronically active Crohn’s disease^{† [off-label]}.

Cyclosporine Dosage and Administration

General

Transplant Patients

• Patients should be managed using a center experienced in the use and interpretation of cyclosporine concentrations and their application to dosage adjustment; however, if management with such a center is not possible, consult specialized references for general monitoring and dosing guidelines.

• Frequency of monitoring blood cyclosporine concentrations depends in part on the time that has elapsed since transplantation, intercurrent illness, and concomitant drugs. Monitor concentrations whenever clinical manifestations suggest that dosage adjustment might be necessary.

• Some clinicians monitor cyclosporine concentrations frequently (e.g., 3 or 4 times weekly to daily) during the early posttransplantation period, reducing monitoring to once monthly by 6–12 months after transplantation.

Rheumatoid Arthritis

• Therapeutic response generally is apparent after 4–8 weeks of cyclosporine therapy. If benefit is not apparent by week 16, discontinue the drug.

• Prior to initiation of cyclosporine therapy, perform careful physical examination of the patient, including measurement of BP on ≥2 occasions and determination of S_cr twice for a baseline.

• Monitor BP and S_cr every 2 weeks during the first 3 months of therapy; thereafter, monitor BP and S_cr monthly in stable patients. Always monitor S_cr and BP following modification of concomitant NSAIA therapy, either an increase in dosage and initiation of new NSAIA.

• Monitor CBC and liver function at least monthly in patients receiving cyclosporine and methotrexate concomitantly.

• Limited experience with long-term cyclosporine therapy for rheumatoid arthritis. Following discontinuance of the drug, control of the disease usually wanes within 4 weeks.

Psoriasis

• Some improvement in clinical manifestations generally is observed after 2 weeks. Satisfactory control and stabilization of psoriasis may require 12–16 weeks of therapy.

• Prior to initiation of cyclosporine therapy, perform careful dermatologic and physical examination of the patient, including measurement of BP on ≥2 occasions. Obtain baseline measurements for S_cr (on 2 occasions), BUN, CBC, and serum concentrations of magnesium, potassium, uric acid, and lipids.

• Evaluate BP every 2 weeks during the first 3 months of therapy; thereafter, evaluate BP monthly in stable patients or more frequently if dosage is adjusted.

• Monitor S_cr and BUN every 2 weeks during the first 3 months of therapy; thereafter, monitor these values monthly in stable patients.

• Monitor CBC and serum concentrations of magnesium, potassium, uric acid, and lipids every 2 weeks during the first 3 months of therapy; thereafter, monitor these values monthly in stable patients or more frequently if dosage is adjusted.

• Discontinuance generally results in relapse within several weeks.

Administration

Administer orally as conventional (nonmodified) or modified formulations or by IV infusion.

Oral Administration

Modified formulations of cyclosporine (Gengraf, Neoral), both as the solution and in the liquid-filled capsules, have increased oral bioavailability compared with the conventional oral solution and liquid-filled capsules of the drug (Sandimmune); conventional (nonmodified) and modified formulations are not bioequivalent. Any change in the formulation of cyclosporine should be performed with caution and under the supervision of a clinician since dosage adjustment may be necessary.

Conventional (nonmodified) capsules of Sandimmune are bioequivalent to Sandimmune oral solution.

Modified oral capsules of Neoral are bioequivalent to Neoral oral solution. Modified oral capsules of Gengraf are bioequivalent to Gengraf oral solution. The Neoral and Gengraf modified oral formulations are bioequivalent to each other.

Conventional (Nonmodified) Capsules (Sandimmune)

Administer orally once daily on a consistent schedule with regard to time of day and in relation to meals.

Modified Capsules (Gengraf and Neoral)

Administer orally twice daily on a consistent schedule with regard to time of day and in relation to meals.

Conventional (Nonmodified) Oral Solution (Sandimmune)

Administer orally once daily on a consistent schedule with regard to time of day and in relation to meals.

Measure dose carefully with the graduated dosing syringe provided by the manufacturer. Remove the protective cover of the dosing syringe and withdraw the prescribed dose from the bottle and transfer to a glass (not plastic) container of suitable beverage. Use of a glass container may minimize adherence of the drug to the container walls. Do not use styrofoam containers; they are porous and may absorb the drug.

To increase palatability, mix the measured dose with milk, chocolate milk, or orange juice, preferably at room temperature but not hot. Avoid frequent changing of the diluting beverage. Stir well and administer immediately. After the initial diluted solution has been administered, rinse the container with additional diluent (e.g., juice) and administer the remaining mixture to ensure that the entire dose has been given.

After use, dry the outside of the dosing syringe with a clean, dry towel and replace the protective cover. Do not rinse the dosing syringe with water, alcohol, or other cleaning agents. If the syringe requires cleaning, allow it to dry completely before reuse, since introduction of water into the product will cause variation in dose.

Modified Oral Solution (Gengraf and Neoral)

Administer orally twice daily on a consistent schedule with regard to time of day and in relation to meals.

Prepare and administer Gengraf or Neoral modified oral solution in a similar manner to the conventional (nonmodified) oral solution; however, the dosing syringe for Gengraf does not have a protective cover.

To increase palatability, mix the measured dose with orange or apple juice at room temperature; do not use milk for dilution, since the resultant mixture can be unpalatable.

After use of Gengraf oral solution, dry the outside of the dosing syringe with a clean towel and store the syringe in a clean, dry place.

IV Administration

Reserve IV administration for patients in whom oral administration is not tolerated or is contraindicated (due to risk of anaphylaxis with IV administration).

Switch patients to an oral formulation as soon as possible after surgery.

Cyclosporine concentrate for injection must be diluted prior to IV infusion.

Dilution

Dilute each mL of the injection concentrate in 20–100 mL of 0.9% sodium chloride or 5% dextrose injection immediately before administration.

Rate of Administration

Transplant patients: Infuse over 2–6 hours.

Crohn’s disease: Infuse over 24 hours.

Dosage

Individualize dosage of cyclosporine.

Pediatric Patients

Transplant Recipients

Conventional Capsules and Oral Solution (Sandimmune)

Oral

Initially, 15 mg/kg administered as a single dose 4–12 hours before transplantation. Lower initial dosages (e.g., 10–14 mg/kg daily) may be preferred for renal allotransplantation.

Postoperatively, continue initial dosage once daily for 1–2 weeks; then, taper by 5% per week (over about 6–8 weeks) to a maintenance dosage of 5–10 mg/kg daily. Maintenance dosages have been tapered to as low as 3 mg/kg daily in selected renal allograft recipients without an apparent increase in graft rejection rate.

In several studies, pediatric patients have required and tolerated higher dosages.

Modified Capsules and Oral Solution (Gengraf and Neoral)

Oral

Newly transplanted patients may receive the modified oral formulation at the same initial dose as for the conventional (nonmodified) oral formulation.

Suggested initial dosages (based on a 1994 survey of average dosages of conventional formulations): 9 mg/kg for renal allograft recipients, 8 mg/kg for hepatic allograft recipients, and 7 mg/kg for cardiac allograft recipients administered in 2 equally divided doses daily. Give initial dose 4–12 hours before transplantation or postoperatively.

Adjust dosage to attain a predefined blood cyclosporine concentration. Titrate dosage based on clinical evaluation of rejection and patient tolerability. Lower maintenance dosages may be possible with modified oral formulations compared with conventional (nonmodified) formulations.

Conversion from Conventional Oral Formulations (Sandimmune) to Modified Oral Formulations (Gengraf, Neoral)

Oral

Initial dosage of the modified formulation should be the same as the previous dosage of the conventional (nonmodified) oral formulation (1:1 conversion). Adjust dosage to attain trough blood concentrations that are similar to those achieved with the conventional oral formulation; however, attainment of therapeutic trough concentrations will result in greater exposure (AUC) to cyclosporine than would occur with the conventional oral formulation.

Monitor trough blood cyclosporine concentrations every 4–7 days until they are the same as they were with the conventional (nonmodified) oral formulation. Monitor patient safety by determining S_cr and BP every 2 weeks for the first 2 months after the conversion. Adjust dosage if trough blood concentrations are outside of the desired range and/or measures of safety worsen. Dosage titration should be guided by trough blood concentrations, tolerability, and clinical response.

Monitor trough blood concentrations closely following conversion from conventional (nonmodified) oral formulations to modified oral formulations in patients with suspected poor absorption of cyclosporine from the conventional formulations. Measure trough blood concentrations in these patients at least twice weekly (daily in patients receiving >10 mg/kg daily) until the trough blood cyclosporine concentration is maintained in the desired range, since higher bioavailability from the modified oral formulations may result in excessive trough concentrations after conversion to this formulation. Use caution with conversional dosages >10 mg/kg daily.

Concentrate for Injection

IV

Initially, 5–6 mg/kg as a single dose 4–12 hours before transplantation. Postoperatively, 5–6 mg/kg once daily until the patient is able to tolerate oral administration. Pediatric patients may require higher dosages.

In patients unable to take cyclosporine orally, may administer the drug by IV infusion at about one-third the recommended oral dosage.

Adults

Transplant Recipients

Conventional Capsules and Oral Solution (Sandimmune)

Oral

Initially, 15 mg/kg administered as a single dose 4–12 hours before transplantation. Lower initial dosages (e.g., 10–14 mg/kg daily) may be preferred for renal allotransplantation.

Postoperatively, continue initial dosage once daily for 1–2 weeks; then, taper by 5% per week (over about 6–8 weeks) to a maintenance dosage of 5–10 mg/kg daily. Maintenance dosages have been tapered to as low as 3 mg/kg daily in selected renal allograft recipients without an apparent increase in graft rejection rate.

Modified Capsules and Oral Solution (Gengrafand Neoral)

Oral

Newly transplanted patients may receive the modified oral formulation at the same initial dose as for the conventional (nonmodified) oral formulation.

Suggested initial dosages (based on a 1994 survey of average dosages of conventional formulations): 9 mg/kg for renal allograft recipients, 8 mg/kg for hepatic allograft recipients, and 7 mg/kg for cardiac allograft recipients administered in 2 equally divided doses daily. Give initial dose 4–12 hours before transplantation or postoperatively.

Adjust dosage to attain a predefined blood cyclosporine concentration. Titrate dosage based on clinical evaluation of rejection and patient tolerability. Lower maintenance dosages may be possible with modified oral formulations compared with conventional (nonmodified) formulations.

Conversion from Conventional Oral Formulations (Sandimmune) to Modified Oral Formulations (Gengraf, Neoral)

Oral

Initial dosage of the modified oral formulation should be the same as the previous dosage of the conventional (nonmodified) oral formulation (1:1 conversion). Adjust dosage to attain trough blood concentrations that are similar to those achieved with the conventional oral formulation; however, attainment of therapeutic trough concentrations will result in greater exposure (AUC) to cyclosporine than would occur with conventional oral formulation.

Monitor trough blood cyclosporine concentrations every 4–7 days until they are the same as they were with the conventional (nonmodified) oral formulation. Monitor patient safety by determining S_cr and BP every 2 weeks for the first 2 months after the conversion. Adjust dosage if trough blood concentrations are outside of the desired range and/or measures of safety worsen. Dosage titration should be guided by trough blood concentrations, tolerability, and clinical response.

Monitor trough blood concentrations closely following conversion from conventional (nonmodified) oral formulations to modified oral formulations in patients with suspected poor absorption of cyclosporine from the conventional formulations. Measure trough blood concentrations in these patients at least twice weekly (daily in patients receiving >10 mg/kg daily) until the trough blood cyclosporine concentration is maintained in the desired range, since higher bioavailability from the modified oral formulations may result in excessive trough concentrations after conversion to this formulation. Use caution with conversional dosages >10 mg/kg daily.

Concentrate for Injection

IV

Initially, 5–6 mg/kg as a single dose 4–12 hours before transplantation. Postoperatively, 5–6 mg/kg once daily until the patient is able to tolerate oral administration.

In patients unable to take cyclosporine orally, may administer the drug by IV infusion at about one-third the recommended oral dosage.

Rheumatoid Arthritis

Modified Capsules and Oral Solution (Gengraf and Neoral)

Oral

Initially, 2.5 mg/kg daily in 2 divided doses. If response is insufficient but tolerance to the drug is good (including S_cr <30% above baseline), may increase dosage by 0.5–0.75 mg/kg daily after 8 weeks and, again, after 12 weeks (maximum 4 mg/kg daily).

Reduce dosage by 25–50% to control adverse effects (e.g., hypertension, clinically important laboratory abnormalities) that occur. Manage persistent hypertension by further reduction of cyclosporine dosage or use of antihypertensive agents. Discontinue if adverse effects are severe or do not respond to dosage reduction.

Psoriasis

Modified Capsules and Oral Solution (Gengraf and Neoral)

Oral

Initially, 1.25 mg/kg twice daily. Continue for ≥4 weeks unless prohibited by adverse effects. If initial dosage does not produce substantial clinical improvement within 4 weeks, increase dosage by approximately 0.5 mg/kg daily once every 2 weeks (maximum 4 mg/kg daily) based on the patient’s tolerance and response.

Use lowest dosage that maintains an adequate response (not necessarily total clearance of psoriasis). Dosages <2.5 mg/kg daily may be equally effective.

Decrease dosage by 25–50% to control adverse effects (e.g., hypertension, clinically important laboratory test abnormalities) that occur. Discontinue if adverse effects are severe or do not respond to dosage reduction.

Crohn’s Disease

Conventional (Nonmodified) Capsules (Sandimmune)

Oral

3.8–8 mg/kg daily has been used.

Concentrate for Injection

IV

Initially, 4 mg/kg daily for about 2–10 days has been used. Patients who respond to initial IV regimen may be switched to oral therapy.

Prescribing Limits

Adults

Rheumatoid Arthritis

Modified Capsules and Oral Solution (Gengraf and Neoral)

Oral

Maximum 4 mg/kg daily.

Psoriasis

Modified Capsules and Oral Solution (Gengraf and Neoral)

Oral

Maximum 4 mg/kg daily.

Special Populations

Renal Impairment

Monitor renal function closely; frequent dosage adjustments may be necessary.

Contraindicated in rheumatoid arthritis or psoriasis patients with abnormal renal function.

Cautions for Cyclosporine

Contraindications

• Known hypersensitivity to cyclosporine or to any ingredient in the formulation.

• Rheumatoid arthritis or psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies.

• Concurrent therapy with methotrexate or other immunosuppressive agents, coal tar, PUVA, UVB, or other radiation in the management of psoriasis.

Warnings/Precautions

Warnings

Renal Effects

Possible nephrotoxicity; elevations of BUN and S_cr appear to be dose related, may be associated with high trough concentrations of the drug, and usually are reversible upon discontinuance of the drug.

In patients with psoriasis, nephrotoxicity may occur at recommended dosages, with increasing risk as dosage and duration of therapy increase.

Risk of nephrotoxicity may be increased in patients receiving other potentially nephrotoxic agents.

Monitor renal function carefully. Potential for structural kidney damage and permanent renal dysfunction in the absence of appropriate monitoring and dosage adjustment.

Carefully evaluate renal allograft recipients who develop increased BUN and S_cr before adjusting cyclosporine dosage; these increases do not necessarily indicate the occurrence of organ rejection. If elevations of BUN and S_cr are persistently high and unresponsive to adjustment of cyclosporine dosage, consider switching to other immunosuppressive therapy. If severe, intractable renal allograft rejection occurs and does not respond to rescue therapy with corticosteroids and monoclonal antibodies, it may be preferable to switch to alternative immunosuppressive therapy or to allow the kidney to be rejected and removed rather than to increase the cyclosporine dosage to an excessive level in an attempt to reverse the rejection episode.

Possible hyperkalemia (may be associated with hyperchloremic metabolic acidosis), hypomagnesemia, decreased serum bicarbonate concentration, and hyperuricemia.

Monitoring of Cyclosporine Concentrations

Results obtained with various assay methods and biologic fluids (blood versus plasma or serum) are not interchangeable; consult specialized references and/or the assay manufacturer’s labeling for interpretative guidelines.

Monitor trough (predose) cyclosporine concentrations. Standardize the sampling time for each patient; consider the effect of once- versus twice-daily dosing and the time for pharmacokinetic reequilibration to steady state following dosage changes.

Monitor predose cyclosporine concentrations periodically in patients receiving conventional (nonmodified) oral formulations (Sandimmune capsules or solution), since absorption is reportedly erratic during long-term therapy.

Monitoring may be especially important in hepatic allograft recipients, since absorption of the drug in these patients may be erratic, especially during the first few weeks following transplantation (because of surgical techniques [e.g., bile duct management] or surgically induced liver dysfunction).

Routinely monitor blood or plasma concentrations in allograft recipients receiving the modified oral formulations (Gengraf, Neoral) and periodically in patients with rheumatoid arthritis being treated with these preparations (to avoid toxicity secondary to high cyclosporine concentrations). In studies in psoriasis patients, cyclosporine concentrations did not correlate well with clinical improvement or adverse effects.

Monitor cyclosporine concentrations carefully following conversion from conventional (nonmodified) oral formulations to modified formulations.

Adjust dosage to avoid toxicity resulting from high blood or plasma concentrations of the drug or to prevent possible organ rejection resulting from low concentrations.

Hepatic Effects

Hepatotoxicity reported in patients with kidney, heart, or liver allografts, usually during the first month of therapy when higher dosages are used. Usually reversible following dosage reduction.

Lymphomas and Other Malignancies

Possible increased development of lymphoma.

Manufacturer cautions that although cyclosporine should be administered with corticosteroids, conventional (nonmodified) oral formulations of the drug (Sandimmune) and the concentrate for injection should not be administered concomitantly with other immunosuppressive agents, since increased risk of lymphoma may result. However, the manufacturers state that modified oral formulations of cyclosporine (Gengraf and Neoral) may be administered with other immunosuppressive agents, although the degree of immunosuppression produced may result in an increased risk of lymphoma and other neoplasms.

Evaluate patients thoroughly for the presence of malignancies before initiating cyclosporine therapy for rheumatoid arthritis, as well as during the treatment course. Concurrent use of cyclosporine and other immunosuppressive agents may increase the risk of malignancies through induction of excessive immunosuppression.

Possible increased risk of developing malignancies of the skin and lymphoproliferative disorders in patients receiving cyclosporine to treat psoriasis. Evaluate such patients thoroughly before initiating cyclosporine therapy, as well as during the treatment course, for the presence of malignancies; consider that psoriatic plaques may obscure malignant lesions. Avoid concomitant therapy with methotrexate or other immunosuppressive agents, coal tar, PUVA, UVB, or other radiation, due to potential for excessive immunosuppression and increased risk of malignancies. Limit exposure to sunlight or other UV light during cyclosporine therapy.

Infectious Complications

Possible increased susceptibility to infection.

Evaluate psoriasis patients for presence of occult infection prior to and throughout therapy.

Manufacturer cautions that although cyclosporine should be administered with corticosteroids, conventional (nonmodified) oral formulations of the drug (Sandimmune) and the concentrate for injection should not be administered concomitantly with other immunosuppressive agents, since increased susceptibility to infection may result. However, the manufacturers state that modified oral formulations (Gengraf and Neoral) may be administered with other immunosuppressives, although the degree of immunosuppression produced may result in increased susceptibility to infection.

Latent Viral Infections

Increased risk of reactivation of latent viral infections, including BK virus-associated nephropathy (BKVN). Principally observed in renal transplant patients (usually within the first year posttransplantation); may result in severe allograft dysfunction and/or graft loss. Risk appears to correlate with degree of overall immunosuppression rather than use of specific immunosuppressant. Monitor closely for signs of BKVN (e.g., deterioration of renal function); if BKVN develops, institute early treatment, and consider reducing immunosuppressive therapy.

Bioequivalency of Formulations

Modified oral formulations of cyclosporine (Gengraf and Neoral liquid-filled capsules and solution) have increased oral bioavailability compared with conventional (nonmodified) oral formulations (Sandimmune liquid-filled capsules and solution); therefore, the modified and conventional (nonmodified) formulations are not bioequivalent and cannot be used interchangeably without appropriate medical supervision.

For a given trough concentration, cyclosporine exposure will be greater with Gengraf and Neoral preparations than with Sandimmune preparations.

Conversion from Gengraf or Neoral to Sandimmune preparations using a 1:1 ratio may result in lower blood concentrations; increase monitoring to avoid the potential of underdosing.

Hematologic Effects

Possible leukopenia, anemia, and thrombocytopenia.

Risk of developing syndrome of thrombocytopenia and microangiopathic hemolytic anemia (pathologically similar to hemolytic uremic syndrome); may result in graft failure. Manifestations include thrombosis of renal microvasculature with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function. Such findings are generalizable to other immunosuppressive agents used after transplantation. Neither the pathogenesis nor optimal management is clear.

CNS Effects

Potential for seizures, particularly when used in combination with high-dose corticosteroids.

Encephalopathy, manifested by impaired consciousness, seizures, visual changes (e.g., blindness), loss of motor function, movement disorders, and psychiatric disturbances, described in patients receiving cyclosporine; in many cases, such manifestations accompanied by white-matter changes. May be associated with high blood or plasma concentrations of the drug, concurrent high-dose corticosteroid therapy, hypertension, and/or hypomagnesemia. May be reversible upon discontinuance of the drug or following dosage reduction.

Optic disc edema with possible visual impairment reported rarely; occurred more frequently in transplant recipients.

Sensitivity Reactions

Anaphylaxis

Risk of anaphylaxis with IV cyclosporine; reserve for patients unable to tolerate oral formulations of the drug.

Continuously observe patients for ≥30 minutes following initiation of the IV infusion; closely monitor at frequent intervals thereafter for possible allergic manifestations. Appropriate equipment for maintenance of an adequate airway and other supportive measures and agents for the treatment of anaphylactic reactions (e.g., epinephrine, oxygen) should be readily available.

If anaphylaxis occurs, discontinue IV infusion immediately and administer appropriate therapy (e.g., epinephrine, oxygen) as indicated.

General Precautions

Hypertension

Mild to moderate hypertension occurs in about 50% of renal transplant recipients and most cardiac transplant patients receiving the drug. Hypertension reported in about 28% of psoriasis patients and systolic hypertension reported in about 33% of rheumatoid arthritis patients receiving the drug.

Generally develops within a few weeks after beginning cyclosporine therapy and affects both SBP and DBP.

May respond to dosage reduction and/or antihypertensive therapy, but response to antihypertensive therapy may be variable. Elevated DBP may be more resistant to treatment than elevated SBP.

Contraindicated in rheumatoid arthritis and psoriasis patients with uncontrolled hypertension.

Malabsorption Syndromes

Patients with malabsorption may have difficulty achieving therapeutic concentrations of cyclosporine with conventional (nonmodified) oral formulations (Sandimmune).

Specific Populations

Pregnancy

Category C.

Lactation

Distributed into milk; women should not breast-feed infants while receiving the drug.

Pediatric Use

No adequate and controlled studies to date; however, cyclosporine has been used in children ≥6 months of age without unusual adverse effects. Modified oral formulations (Gengraf and Neoral) used in children ≥1 year of age.

Consider the possibility that serious nephrotoxicity, hypertension, and/or seizures may occur.

Safety and efficacy of cyclosporine for the management of juvenile rheumatoid arthritis or psoriasis in children <18 years of age not established.

Geriatric Use

Assess renal function with particular care, due to greater frequency of decreased renal function observed in geriatric patients.

Patients ≥65 years of age were more likely to develop systolic hypertension while receiving cyclosporine to treat rheumatoid arthritis in clinical studies and also were more likely to have S_cr elevations of ≥50% above baseline after 3–4 months of therapy.

Renal Impairment

Use with caution; assess renal function prior to and periodically during prolonged therapy. Dosage adjustment may be necessary depending on degree of renal impairment.

Carefully evaluate renal allograft recipients who develop increased BUN and S_cr before initiating adjustment of cyclosporine dosage, since these increases do not necessarily indicate the occurrence of organ rejection.

Contraindicated in rheumatoid arthritis or psoriasis patients with abnormal renal function.

Common Adverse Effects

Transplant recipients: Renal impairment, tremor, hirsutism, hypertension, gum hyperplasia.

Rheumatoid arthritis: Renal impairment, hypertension, headache, GI disturbances, hirsutism/hypertrichosis.

Psoriasis: Renal impairment, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, flu-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, musculoskeletal or joint pain.

Drug Interactions

Extensively metabolized by CYP3A.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A inhibitors: Potential pharmacokinetic interaction (increased cyclosporine concentrations in biologic fluid).

CYP3A inducers: Potential pharmacokinetic interaction (decreased cyclosporine concentrations in biologic fluid).

Nephrotoxic Drugs

Potentiation of renal dysfunction well substantiated; may be related to nephrotoxic potential of the interacting drug or to accumulation of cyclosporine induced by the interacting drug. Use with caution.

Specific Drugs and Foods

Cyclosporine Pharmacokinetics

Absorption

Bioavailability

Variably and incompletely absorbed following oral administration. Undergoes extensive first-pass metabolism following oral administration.

Extent of absorption depends on the individual patient, patient population (e.g., transplant type), posttransplantation time (e.g., increasing during the early posttransplantation period in renal transplant recipients), bile flow (micellar absorption of the drug involving bile), GI state (e.g., decreased with diarrhea), and formulation administered.

Peak blood and plasma concentrations are attained about 3.5 hours following oral administration of conventional (nonmodified) formulations.

Modified oral formulations (Gengraf, Neoral) have greater bioavailability than the conventional (nonmodified) oral formulations (Sandimmune). (See Bioequivalency of Formulations under Cautions.)

Conventional (nonmodified) liquid-filled capsules of Sandimmune are bioequivalent to Sandimmune oral solution.

Modified oral capsules of Neoral are bioequivalent to Neoral oral solution. Modified oral capsules of Gengraf are bioequivalent to Gengraf oral solution. The Neoral and Gengraf modified oral formulations are bioequivalent to each other.

Food

Data regarding effect of food on cyclosporine absorption are discordant.

Plasma Concentrations

Possible decreased frequency of organ rejection when trough blood concentrations (determined by HPLC) are >100 ng/mL.

Trough blood or plasma concentrations (i.e., at 24 hours) of 250–800 or 50–300 ng/mL, respectively, (determined by RIA) appear to minimize the frequency of graft rejection and cyclosporine-induced adverse effects.

Possible association between trough serum concentrations >500 ng/mL (determined by RIA) and cyclosporine-induced nephrotoxicity.

Distribution

Extent

Widely distributed into body fluids and tissues; most of drug is distributed outside the blood volume.

Crosses the placenta and is distributed into milk.

Plasma Protein Binding

Approximately 90–98% (mainly lipoproteins).

Elimination

Metabolism

Extensively metabolized in the liver, principally by CYP3A, and less extensively in the GI tract and the kidney to at least 30 metabolites.

Elimination Route

Excreted principally via bile, almost entirely as metabolites; about 6% of a dose excreted in urine.

Half-life

Biphasic; terminal half-life averages 8.4–27 hours (range: 4–50 hours).

Stability

Storage

Oral

Capsules, liquid-filled (nonmodified)

25°C (may be exposed to 15–30°C).

Oral Solution, Concentrate (nonmodified)

<30°C. Do not refrigerate; protect from freezing.

Discard 2 months after opening.

Capsules, liquid-filled (modified)

Neoral: 20–25°C.

Gengraf: 15–30°C.

Oral Solution (modified)

Neoral: 20–25°C. Do not refrigerate.

Gengraf: 15–30°C. Do not refrigerate.

Formation of gel, light flocculation, or formation of light sediment may occur at <20°C; warm Neoral oral solution to 25°C and Gengraf oral solution to 15–30°C to reverse these changes.

Discard 2 months after opening.

Parenteral

Concentrate for Injection

<30°C; protect from light.

Polyoxyl 35 castor oil (in cyclosporine injection) can cause leaching of bis(2-ethylhexyl) phthalate (DEHP) from PVC containers. Cyclosporine 2 mg/mL is stable for 24 hours in dextrose 5% or sodium chloride 0.9% in glass or PVC containers; however, to minimize patient exposure to DEHP, some clinicians suggest that diluted solutions in PVC containers be administered immediately after preparation.

Actions

• Inhibits cell-mediated immune responses such as allograft rejection, delayed hypersensitivity (e.g., tuberculin-induced), experimental allergic encephalomyelitis, Freund’s adjuvant-induced arthritis, and graft-vs-host disease in animal studies.

• Exact mechanism(s) of immunosuppressive action not fully elucidated; appears to mainly involve inhibition of lymphocytic proliferation and function.

• Produces nephrotoxic effects, which generally appear to be dose dependent and reversible.

Advice to Patients

• Risk of hypertension and renal impairment.

• Necessity of routine laboratory testing (e.g., BUN, S_cr, bilirubin, liver enzymes) for assessment of renal and hepatic function.

• Increased risk of neoplasia.

• Necessity of making any change in the cyclosporine formulation under the supervision of a clinician, since dosage adjustment may be necessary and caution should be observed during the transition.

• Importance of administering oral cyclosporine on a consistent schedule with regard to time of day and in relation to meals.

• Importance of following manufacturer’s instructions for dilution and administration of conventional (nonmodified) oral solution and modified oral solution.

• Importance of avoiding grapefruit juice during cyclosporine therapy.

• For psoriasis patients, importance of appropriate protection from the sun and avoidance of excessive solar exposure.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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