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Uses

See the MEDWATCH notification at the beginning of the monograph.

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†.

Has been used for the treatment of moderate to severe, acute graft-vs-host disease† 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† and other DMARDs†.

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†.

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. (See Monitoring of Cyclosporine Concentrations under Cautions.)

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. (See Pharmacokinetics.) 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

For solution and drug compatibility information, see Compatibility under Stability.

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. (See Parenteral under Storage.)

Rate of Administration

Transplant patients: Infuse over 2–6 hours.

Crohn’s disease: Infuse over 24 hours.

Dosage

See the MEDWATCH notification at the beginning of the monograph.

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 (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 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

Dosage in Renal Impairment

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

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