Cyclosporine (Monograph)

Brand names: Gengraf, Neoral, SandIMMUNE
Drug class: Calcineurin Inhibitors, Miscellaneous
- Disease-modifying Antirheumatic Drugs
- DMARDs
- Immunosuppressive Agents

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

Warning

Only clinicians experienced in management of systemic immunosuppressive therapy for the indicated disease and/or management of organ transplant patients should prescribe cyclosporine.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹
Patients should be managed in facilities with adequate laboratory and supportive medical resources; the clinician responsible for maintenance therapy should have complete information for patient follow-up.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹

Immunosuppression may result in increased susceptibility to infection and possible development of lymphoma or other neoplasms.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁵⁹⁵ (See Lymphomas and Other Malignancies under Cautions.)
Manufacturer cautions that conventional (nonmodified) oral formulations and the concentrate for injection should be administered with corticosteroids but not with other immunosuppressive agents in organ transplant recipients.⁴⁷⁹ Manufacturers state that modified oral formulations of cyclosporine (Neoral and Gengraf) may be administered with oral immunosuppressive agents in transplant patients, although the degree of immunosuppression produced may result in increased susceptibility to infection and possible development of lymphoma and other neoplasms.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁵⁹⁴

Conventional (nonmodified) oral formulations (Sandimmune liquid-filled capsules and solution) have decreased bioavailability compared with modified oral formulations (Neoral and Gengraf liquid-filled capsules and solution).⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ Conventional (nonmodified) and modified formulations are not bioequivalent and cannot be used interchangeably without physician supervision.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ (See Conversion from Conventional Oral Formulations [Sandimmune] to Modified Oral Formulations [Gengraf, Neoral] under Dosage and Administration.)
Absorption of cyclosporine during chronic administration of Sandimmune capsules and oral solution may be erratic.⁴⁷⁹ Patients, especially liver transplant recipients, receiving these formulations over a period of time should be monitored at repeated intervals for blood cyclosporine concentrations and possible organ rejection due to low absorption of cyclosporine.⁴⁷⁹
For a given trough concentration, cyclosporine exposure will be greater with Neoral or Gengraf preparations than with Sandimmune preparations.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ Exercise particular caution if a patient is receiving exceptionally high doses of Sandimmune and is converted to Gengraf or Neoral.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ (See Conversion from Conventional Oral Formulations [Sandimmune] to Modified Oral Formulations [Gengraf, Neoral] under Dosage and Administration.)
Patients receiving Gengraf or Neoral liquid-filled capsules or oral solution for organ transplant or in the management of rheumatoid arthritis should also have blood cyclosporine concentrations monitored to avoid toxicity due to high concentrations.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ (See Monitoring of Cyclosporine Concentrations under Cautions.)

Previous therapy with psoralen and UVA light (PUVA) and, to a lesser extent, methotrexate, other immunosuppressive agents, UVB, coal tar, or radiation therapy may increase risk of skin malignancies in patients receiving cyclosporine.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸
Recommended dosages can cause hypertension and nephrotoxicity; risk increases with dose and duration of therapy.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ Monitor renal function (see General: Psoriasis, under Dosage and Administration).⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸

Introduction

Immunosuppressive agent and disease-modifying antirheumatic drug (DMARD);¹ ² ³¹ ⁶⁵ cyclic polypeptide.⁴⁷⁸ ⁴⁷⁹

Uses for Cyclosporine

Renal, Hepatic, and Cardiac Allotransplantation

Prevention of allograft rejection in kidney,¹ ² ⁹ ¹¹ ¹⁶ ²² ⁶⁸ ⁶⁹ liver,¹ ² ²³ ³⁵ or heart transplant patients.¹ ² ¹⁸ ³⁶

Treatment of chronic allograft rejection in patients previously treated with other immunosuppressive agents (e.g., azathioprine).¹

Manufacturers state that corticosteroid therapy should be used concomitantly with IV cyclosporine¹ ¹⁷⁰ and conventional (nonmodified) oral formulations (Sandimmune)¹⁷⁰ and be administered concomitantly, at least initially, with modified oral formulations (Gengraf or Neoral).³⁹¹ ⁴⁷⁶ ⁴⁷⁷ 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.⁹ ¹¹ ²²

Bone Marrow Allotransplantation

Prevention of acute graft-vs-host disease following bone marrow transplantation^{† [off-label]}.² ¹⁹ ²⁵ ²⁶ ⁹⁷ ⁹⁸ ⁹⁹ ¹⁰⁰

Has been used for the treatment of moderate to severe, acute graft-vs-host disease^{† [off-label]} following bone marrow transplantation.²⁴ ¹⁰¹ ¹⁰²

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.³⁶⁷ ³⁶⁸ ³⁶⁹ ³⁷⁰ ³⁷¹ ³⁷² ³⁷³ ³⁷⁴ ³⁷⁵ ³⁷⁶ ⁴³¹

Treatment of rheumatoid arthritis in adults who had an insufficient response to or did not tolerate NSAIAs^{† [off-label]} and other DMARDs^{† [off-label]}.³⁶⁷ ³⁶⁹ ³⁷³ ³⁷⁴ ³⁷⁵ ³⁷⁶

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.²⁸ ²²⁴ ²²⁵ ²²⁶ ²²⁷ ²²⁸ ²²⁹ ²³⁰ ²³¹ ²³² ²³³ ²³⁴ ²³⁵ ²³⁶ ²³⁷ ²³⁸ ²³⁹ ²⁴⁰ ²⁴¹ ²⁴² ²⁴³ ²⁴⁴ ²⁴⁵ ²⁴⁶ ²⁴⁷ ²⁴⁸ ²⁴⁹ ²⁵⁰ ²⁵¹ ²⁵² ²⁵³ ²⁵⁴ ²⁵⁵ ²⁵⁶ ⁴³¹

Crohn’s Disease

Has been used with some success in the management of refractory inflammatory,⁴⁸⁴ ⁴⁹² fistulizing,⁴⁸⁴ ⁴⁸⁶ ⁴⁸⁹ and chronically active Crohn’s disease^{† [off-label]}.¹⁹⁹ ²¹⁰ ²¹¹ ³⁹⁷ ⁴⁰⁷ ⁴⁸⁴ ⁴⁸⁵ ⁴⁸⁷ ⁴⁹²

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;⁴²⁴ however, if management with such a center is not possible, consult specialized references for general monitoring and dosing guidelines.⁴²⁴
Frequency of monitoring blood cyclosporine concentrations depends in part on the time that has elapsed since transplantation, intercurrent illness, and concomitant drugs.⁴²⁴ Monitor concentrations whenever clinical manifestations suggest that dosage adjustment might be necessary.⁹ ⁴²⁴
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.⁹ ⁴²⁴ (See Monitoring of Cyclosporine Concentrations under Cautions.)

Rheumatoid Arthritis

Therapeutic response generally is apparent after 4–8 weeks of cyclosporine therapy.⁴³¹ If benefit is not apparent by week 16, discontinue the drug.⁴³¹
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.⁴³¹ ⁴⁶⁴
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.⁴³¹ Always monitor S_cr and BP following modification of concomitant NSAIA therapy, either an increase in dosage and initiation of new NSAIA.⁴³¹
Monitor CBC and liver function at least monthly in patients receiving cyclosporine and methotrexate concomitantly.⁴⁵²
Limited experience with long-term cyclosporine therapy for rheumatoid arthritis.⁴³¹ Following discontinuance of the drug, control of the disease usually wanes within 4 weeks.⁴³¹

Psoriasis

Some improvement in clinical manifestations generally is observed after 2 weeks.⁴³¹ Satisfactory control and stabilization of psoriasis may require 12–16 weeks of therapy.⁴³¹
Prior to initiation of cyclosporine therapy, perform careful dermatologic and physical examination of the patient, including measurement of BP on ≥2 occasions.⁴³¹ ⁴⁵⁸ Obtain baseline measurements for S_cr (on 2 occasions), BUN, CBC, and serum concentrations of magnesium, potassium, uric acid, and lipids.⁴³¹
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.⁴³¹
Monitor S_cr and BUN every 2 weeks during the first 3 months of therapy; thereafter, monitor these values monthly in stable patients.⁴³¹
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.⁴³¹
Discontinuance generally results in relapse within several weeks.⁴³¹

Administration

Administer orally as conventional (nonmodified) or modified formulations or by IV infusion.⁴⁰⁷ ⁴⁰⁸ ⁴⁰⁹ ⁴¹⁰ ⁴¹¹ ⁴¹² ⁴¹³ ⁴¹⁴ ⁴¹⁵ ⁴¹⁶ ⁴¹⁷ ⁴¹⁸ ⁴¹⁹ ⁴²⁰ ⁴²¹ ⁴²² ⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ ⁴⁸³

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.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ (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.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹

Conventional (nonmodified) capsules of Sandimmune are bioequivalent to Sandimmune oral solution.⁴⁷⁹

Modified oral capsules of Neoral are bioequivalent to Neoral oral solution.⁴⁷⁸ Modified oral capsules of Gengraf are bioequivalent to Gengraf oral solution.⁴⁷⁶ ⁴⁷⁷ The Neoral and Gengraf modified oral formulations are bioequivalent to each other.⁴⁸⁰ ⁴⁸¹ ⁴⁸²

Conventional (Nonmodified) Capsules (Sandimmune)

Administer orally once daily on a consistent schedule with regard to time of day and in relation to meals.¹⁷⁰ ¹⁷¹

Modified Capsules (Gengraf and Neoral)

Administer orally twice daily on a consistent schedule with regard to time of day and in relation to meals.³⁹¹ ⁴⁷⁶

Conventional (Nonmodified) Oral Solution (Sandimmune)

Administer orally once daily on a consistent schedule with regard to time of day and in relation to meals.¹⁷⁰ ¹⁷¹

Measure dose carefully² with the graduated dosing syringe provided by the manufacturer.¹ 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.¹ ¹⁰⁷ ³⁹¹ Use of a glass container may minimize adherence of the drug to the container walls.¹ ² ¹⁰⁷ ¹⁷⁰ ³⁹¹ Do not use styrofoam containers; they are porous and may absorb the drug.¹⁰⁷ ¹⁷⁰ ³⁹¹

To increase palatability, mix the measured dose with milk, chocolate milk, or orange juice, preferably at room temperature but not hot.¹ ¹⁰⁷ Avoid frequent changing of the diluting beverage.¹⁷⁰ Stir well and administer immediately.¹ ¹⁷⁰ ³⁹¹ 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.¹ ¹⁰⁷

After use, dry the outside of the dosing syringe with a clean, dry towel and replace the protective cover.¹ ¹⁰⁷ Do not rinse the dosing syringe with water, alcohol, or other cleaning agents.¹ ¹⁰⁷ If the syringe requires cleaning, allow it to dry completely before reuse, since introduction of water into the product will cause variation in dose.¹⁷⁰

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.³⁹¹ ⁴⁷⁷

Prepare and administer Gengraf or Neoral modified oral solution in a similar manner to the conventional (nonmodified) oral solution;³⁹¹ however, the dosing syringe for Gengraf does not have a protective cover.⁴⁷⁷

To increase palatability, mix the measured dose with orange or apple juice at room temperature;³⁹¹ ⁴⁷⁷ do not use milk for dilution, since the resultant mixture can be unpalatable.³⁹¹ ⁴⁷⁷

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.⁴⁷⁷

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).¹ ¹⁷⁰

Switch patients to an oral formulation as soon as possible after surgery.¹ ¹⁷⁰

Cyclosporine concentrate for injection must be diluted prior to IV infusion.¹ ¹⁷⁰

Dilution

Dilute each mL of the injection concentrate in 20–100 mL of 0.9% sodium chloride or 5% dextrose injection immediately before administration.¹ ¹⁷⁰ (See Parenteral under Storage.)

Rate of Administration

Transplant patients: Infuse over 2–6 hours.¹ ¹⁷⁰

Crohn’s disease: Infuse over 24 hours.⁴⁹²

Dosage

Individualize dosage of cyclosporine.² ⁹ ¹⁷⁰ ³⁹¹ ⁴²⁴ ⁴²⁵ ⁴⁷⁶ ⁴⁷⁷

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.¹ ⁹ Lower initial dosages (e.g., 10–14 mg/kg daily) may be preferred for renal allotransplantation.¹⁷⁰

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.¹ ⁹ ¹⁷⁰ 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.¹ ¹³³ ¹⁷⁰

In several studies, pediatric patients have required and tolerated higher dosages.¹ ¹⁷⁰

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.³⁹¹ ⁴⁷⁶ ⁴⁷⁷

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.³⁹¹ Give initial dose 4–12 hours before transplantation or postoperatively.³⁹¹ ⁴⁷⁶ ⁴⁷⁷

Adjust dosage to attain a predefined blood cyclosporine concentration.³⁹¹ ⁴⁷⁶ ⁴⁷⁷ Titrate dosage based on clinical evaluation of rejection and patient tolerability.³⁹¹ ⁴⁷⁶ ⁴⁷⁷ Lower maintenance dosages may be possible with modified oral formulations compared with conventional (nonmodified) formulations.³⁹¹ ⁴⁷⁶ ⁴⁷⁷

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).³⁹¹ ⁴⁷⁶ ⁴⁷⁷ 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.³⁹¹ ⁴⁷⁶ ⁴⁷⁷

Monitor trough blood cyclosporine concentrations every 4–7 days until they are the same as they were with the conventional (nonmodified) oral formulation.³⁹¹ ⁴⁷⁶ ⁴⁷⁷ Monitor patient safety by determining S_cr and BP every 2 weeks for the first 2 months after the conversion.³⁹¹ ⁴⁷⁶ ⁴⁷⁷ Adjust dosage if trough blood concentrations are outside of the desired range and/or measures of safety worsen.³⁹¹ ⁴⁷⁶ ⁴⁷⁷ Dosage titration should be guided by trough blood concentrations, tolerability, and clinical response.³⁹¹ ⁴⁷⁶ ⁴⁷⁷

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.³⁹¹ ⁴⁷⁶ ⁴⁷⁷ 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.³⁹¹ ⁴⁷⁶ ⁴⁷⁷ Use caution with conversional dosages >10 mg/kg daily.³⁹¹ ⁴⁷⁶ ⁴⁷⁷

Concentrate for Injection

Initially, 5–6 mg/kg as a single dose 4–12 hours before transplantation.¹ ¹⁷⁰ Postoperatively, 5–6 mg/kg once daily until the patient is able to tolerate oral administration.¹ ¹⁷⁰ Pediatric patients may require higher dosages.¹⁷⁰

In patients unable to take cyclosporine orally, may administer the drug by IV infusion at about one-third the recommended oral dosage.¹ ¹⁷⁰

Adults

Transplant Recipients

Conventional Capsules and Oral Solution (Sandimmune)

Oral

Initially, 15 mg/kg administered as a single dose 4–12 hours before transplantation.¹ ⁹ Lower initial dosages (e.g., 10–14 mg/kg daily) may be preferred for renal allotransplantation.¹⁷⁰

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.³⁹¹ ⁴⁷⁶ ⁴⁷⁷

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.³⁹¹ ⁴⁷⁶ ⁴⁷⁷ Give initial dose 4–12 hours before transplantation or postoperatively.³⁹¹ ⁴⁷⁶ ⁴⁷⁷

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).³⁹¹ ⁴⁷⁶ ⁴⁷⁷ 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.³⁹¹ ⁴⁷⁶ ⁴⁷⁷

Concentrate for Injection

Initially, 5–6 mg/kg as a single dose 4–12 hours before transplantation.¹ ¹⁷⁰ Postoperatively, 5–6 mg/kg once daily until the patient is able to tolerate oral administration.¹ ¹⁷⁰

In patients unable to take cyclosporine orally, may administer the drug by IV infusion at about one-third the recommended oral dosage.¹ ¹⁷⁰

Rheumatoid Arthritis

Modified Capsules and Oral Solution (Gengraf and Neoral)

Oral

Initially, 2.5 mg/kg daily in 2 divided doses.⁴³¹ ⁴⁷⁶ ⁴⁷⁷ 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).⁴³¹ ⁴⁷⁶ ⁴⁷⁷

Reduce dosage by 25–50% to control adverse effects (e.g., hypertension, clinically important laboratory abnormalities) that occur.⁴³¹ ⁴⁷⁶ ⁴⁷⁷ Manage persistent hypertension by further reduction of cyclosporine dosage or use of antihypertensive agents.⁴³¹ ⁴⁷⁶ ⁴⁷⁷ Discontinue if adverse effects are severe or do not respond to dosage reduction.⁴³¹ ⁴⁷⁶ ⁴⁷⁷

Psoriasis

Modified Capsules and Oral Solution (Gengraf and Neoral)

Oral

Initially, 1.25 mg/kg twice daily.⁴³¹ ⁴⁵⁸ ⁴⁷⁶ ⁴⁷⁷ Continue for ≥4 weeks unless prohibited by adverse effects.⁴³¹ ⁴⁷⁶ ⁴⁷⁷ 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.⁴³¹ ⁴⁷⁶ ⁴⁷⁷

Use lowest dosage that maintains an adequate response (not necessarily total clearance of psoriasis).⁴³¹ ⁴⁵⁸ ⁴⁷⁶ ⁴⁷⁷ Dosages <2.5 mg/kg daily may be equally effective.⁴³¹ ⁴⁷⁶ ⁴⁷⁷

Decrease dosage by 25–50% to control adverse effects (e.g., hypertension, clinically important laboratory test abnormalities) that occur.⁴³¹ ⁴⁷⁶ ⁴⁷⁷ Discontinue if adverse effects are severe or do not respond to dosage reduction.⁴³¹ ⁴⁷⁶ ⁴⁷⁷

Crohn’s Disease

Conventional (Nonmodified) Capsules (Sandimmune)

Oral

3.8–8 mg/kg daily has been used.⁴⁹²

Concentrate for Injection

Initially, 4 mg/kg daily for about 2–10 days has been used.⁴⁹² Patients who respond to initial IV regimen may be switched to oral therapy.⁴⁹²

Prescribing Limits

Adults

Rheumatoid Arthritis

Modified Capsules and Oral Solution (Gengraf and Neoral)

Oral

Maximum 4 mg/kg daily.⁴³¹ ⁴⁷⁶ ⁴⁷⁷

Psoriasis

Modified Capsules and Oral Solution (Gengraf and Neoral)

Oral

Maximum 4 mg/kg daily.⁴³¹ ⁴⁷⁶ ⁴⁷⁷

Special Populations

Renal Impairment

Monitor renal function closely; frequent dosage adjustments may be necessary.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹

Contraindicated in rheumatoid arthritis or psoriasis patients with abnormal renal function.⁴³¹ ⁴⁷⁶ ⁴⁷⁷

Cautions for Cyclosporine

Contraindications

Known hypersensitivity to cyclosporine or to any ingredient in the formulation.¹ ¹⁷⁰ ³⁹¹ ⁴⁷⁶ ⁴⁷⁷
Rheumatoid arthritis or psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies.⁴³¹ ⁴⁷⁶ ⁴⁷⁷
Concurrent therapy with methotrexate or other immunosuppressive agents, coal tar, PUVA, UVB, or other radiation in the management of psoriasis.⁴³¹ ⁴⁷⁶ ⁴⁷⁷

Warnings/Precautions

Warnings

Renal Effects

Possible nephrotoxicity;¹ ² ¹²⁹ 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.¹ ³ ⁹ ⁷⁶

In patients with psoriasis, nephrotoxicity may occur at recommended dosages, with increasing risk as dosage and duration of therapy increase.⁴³¹

Risk of nephrotoxicity may be increased in patients receiving other potentially nephrotoxic agents.¹ (See Interactions.)

Monitor renal function carefully.⁴³¹ Potential for structural kidney damage and permanent renal dysfunction in the absence of appropriate monitoring and dosage adjustment.⁴⁷⁸

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.¹ ¹⁷⁰ ³⁹¹ If elevations of BUN and S_cr are persistently high and unresponsive to adjustment of cyclosporine dosage, consider switching to other immunosuppressive therapy.¹ ¹⁷⁰ ³⁹¹ 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 therapy³⁹¹ 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.¹ ¹⁷⁰ ³⁹¹

Possible hyperkalemia² ¹¹ ⁸⁸ ¹²⁹ ¹³² ¹⁴³ ¹⁶⁷ (may be associated with hyperchloremic metabolic acidosis),¹⁷⁰ ³⁹¹ hypomagnesemia,¹³² ¹³⁶ ¹⁴⁴ ¹⁴⁵ decreased serum bicarbonate concentration,² ¹¹ and hyperuricemia.² ¹¹ ¹³² ¹³⁴ ¹⁴⁶ ¹⁴⁷ ¹⁴⁸ ¹⁴⁹ ¹⁷⁰ ³⁹¹

Monitoring of Cyclosporine Concentrations

Results obtained with various assay methods and biologic fluids (blood versus plasma or serum) are not interchangeable;¹⁰ ⁴⁷ ⁶⁷ ⁷⁶ ⁸⁵ ⁸⁷ ⁴²⁵ consult specialized references and/or the assay manufacturer’s labeling for interpretative guidelines.¹⁷⁰ ³⁹¹ ⁴²⁴

Monitor trough (predose) cyclosporine concentrations.³⁹¹ ⁴²⁴ 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.⁴²⁴

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.¹ ¹⁷⁰ ¹⁷¹ ⁴²⁴

Monitoring may be especially important in hepatic allograft recipients,¹ ¹⁷⁰ 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).¹²

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).⁴³¹ ⁴⁷⁶ ⁴⁷⁷ In studies in psoriasis patients, cyclosporine concentrations did not correlate well with clinical improvement or adverse effects.⁴⁷⁸

Monitor cyclosporine concentrations carefully following conversion from conventional (nonmodified) oral formulations to modified formulations.³⁹¹ ⁴⁷⁶ ⁴⁷⁷ (See Conversion from Conventional Oral Formulations [Sandimmune] to Modified Oral Formulations [Gengraf, Neoral)] under Dosage and Administration.)

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.¹ ¹⁷⁰ ³⁹¹ ⁴²⁴

Hepatic Effects

Hepatotoxicity reported in patients with kidney, heart, or liver allografts, usually during the first month of therapy when higher dosages are used.¹ ¹⁶ Usually reversible following dosage reduction.¹ ¹⁶

Lymphomas and Other Malignancies

Possible increased development of lymphoma.¹ ¹⁷⁰ ³⁹¹

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.¹ ¹⁷⁰ 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.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸

Evaluate patients thoroughly for the presence of malignancies before initiating cyclosporine therapy for rheumatoid arthritis, as well as during the treatment course.⁴³¹ Concurrent use of cyclosporine and other immunosuppressive agents may increase the risk of malignancies through induction of excessive immunosuppression.⁴³¹

Possible increased risk of developing malignancies of the skin and lymphoproliferative disorders in patients receiving cyclosporine to treat psoriasis.⁴³¹ 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.⁴³¹ 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.⁴³¹ Limit exposure to sunlight or other UV light during cyclosporine therapy.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸

Infectious Complications

Possible increased susceptibility to infection.¹ ¹⁷⁰ ³⁹¹

Evaluate psoriasis patients for presence of occult infection prior to and throughout therapy.⁴⁷⁸

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.¹ ¹⁷⁰ 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.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸

Latent Viral Infections

Increased risk of reactivation of latent viral infections, including BK virus-associated nephropathy (BKVN).⁵⁸⁴ ⁵⁸⁵ ⁵⁸⁶ ⁵⁸⁷ ⁵⁸⁸ ⁵⁸⁹ ⁵⁹⁰ ⁵⁹¹ ⁵⁹² ⁵⁹⁴ ⁵⁹⁵ Principally observed in renal transplant patients (usually within the first year posttransplantation); may result in severe allograft dysfunction and/or graft loss.⁵⁸⁴ ⁵⁸⁵ ⁵⁸⁶ ⁵⁸⁷ ⁵⁸⁸ ⁵⁸⁹ ⁵⁹⁰ ⁵⁹¹ ⁵⁹² ⁵⁹⁴ ⁵⁹⁵ Risk appears to correlate with degree of overall immunosuppression rather than use of specific immunosuppressant.⁵⁸⁵ ⁵⁸⁶ ⁵⁸⁷ ⁵⁸⁸ ⁵⁸⁹ ⁵⁹⁰ ⁵⁹¹ ⁵⁹² Monitor closely for signs of BKVN (e.g., deterioration of renal function);⁵⁸⁴ ⁵⁸⁵ ⁵⁸⁶ ⁵⁸⁸ ⁵⁹⁴ ⁵⁹⁵ if BKVN develops, institute early treatment, and consider reducing immunosuppressive therapy.⁵⁸⁴ ⁵⁸⁵ ⁵⁸⁶ ⁵⁸⁷ ⁵⁸⁸ ⁵⁹⁰ ⁵⁹¹ ⁵⁹² ⁵⁹⁴ ⁵⁹⁵

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.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ (See Conversion from Conventional Oral Formulations [Sandimmune] to Modified Oral Formulations [Gengraf, Neoral] under Dosage and Administration.)

For a given trough concentration, cyclosporine exposure will be greater with Gengraf and Neoral preparations than with Sandimmune preparations.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸

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.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹

Hematologic Effects

Possible leukopenia, anemia, and thrombocytopenia.¹

Risk of developing syndrome of thrombocytopenia and microangiopathic hemolytic anemia¹ ¹⁷⁰ ³³⁷ ³³⁸ ³³⁹ ³⁴⁰ ³⁹¹ (pathologically similar to hemolytic uremic syndrome); may result in graft failure.⁴³¹ Manifestations include thrombosis of renal microvasculature with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function.¹⁷⁰ ³³⁷ ³³⁸ ³³⁹ ³⁴⁰ ³⁹¹ Such findings are generalizable to other immunosuppressive agents used after transplantation.¹⁷⁰ ³⁹¹ Neither the pathogenesis nor optimal management is clear.¹ ³⁹¹

CNS Effects

Potential for seizures, particularly when used in combination with high-dose corticosteroids.¹ ¹⁰⁴ ¹⁰⁵ ¹⁰⁶ ¹⁰⁷ ¹²⁹ ¹³⁰ ¹³¹ ¹³⁸ ¹⁷⁰ ³⁹¹

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.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ May be associated with high blood or plasma concentrations of the drug,¹³⁸ ¹⁵³ ¹⁶¹ ¹⁶² ¹⁶³ ¹⁶⁴ ¹⁶⁵ ⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ concurrent high-dose corticosteroid therapy,¹ ¹²⁹ ¹³⁰ ¹³¹ ¹⁵³ ¹⁵⁴ ⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ hypertension,⁷⁰ ⁷⁴ ¹²⁹ ¹⁵⁰ ¹⁵³ ¹⁶⁴ ¹⁶⁵ ⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ and/or hypomagnesemia.¹⁰⁶ ¹²⁹ ¹³⁰ ¹³¹ ¹³² ¹³⁸ ¹⁴⁴ ¹⁴⁵ ¹⁵³ ¹⁵⁵ ⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ May be reversible upon discontinuance of the drug or following dosage reduction.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹

Optic disc edema with possible visual impairment reported rarely; occurred more frequently in transplant recipients.⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹

Sensitivity Reactions

Anaphylaxis

Risk of anaphylaxis with IV cyclosporine; reserve for patients unable to tolerate oral formulations of the drug.¹ ¹⁷⁰

Continuously observe patients for ≥30 minutes following initiation of the IV infusion; closely monitor at frequent intervals thereafter for possible allergic manifestations.¹ ¹⁷⁰ 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.¹ ¹⁷⁰

If anaphylaxis occurs, discontinue IV infusion immediately and administer appropriate therapy (e.g., epinephrine, oxygen) as indicated.¹ ¹⁷⁰

General Precautions

Hypertension

Mild to moderate hypertension occurs in about 50% of renal transplant recipients and most cardiac transplant patients receiving the drug.¹ Hypertension reported in about 28% of psoriasis patients and systolic hypertension reported in about 33% of rheumatoid arthritis patients receiving the drug.⁴³¹

Generally develops within a few weeks after beginning cyclosporine therapy¹²⁹ ¹³² ¹⁵⁰ ¹⁵¹ ¹⁵² ¹⁵⁶ ¹⁵⁷ ¹⁵⁹ ¹⁶⁰ ¹⁶⁷ and affects both SBP and DBP.¹³² ¹⁶⁷

May respond to dosage reduction and/or antihypertensive therapy,¹⁰⁷ but response to antihypertensive therapy may be variable.¹³² ¹⁵⁰ ¹⁵¹ ¹⁵² ¹⁵⁶ ¹⁶⁰ Elevated DBP may be more resistant to treatment than elevated SBP.¹²⁹ ¹³² ¹⁴⁹ ¹⁵⁶

Contraindicated in rheumatoid arthritis and psoriasis patients with uncontrolled hypertension.⁴⁷⁸

Malabsorption Syndromes

Patients with malabsorption may have difficulty achieving therapeutic concentrations of cyclosporine with conventional (nonmodified) oral formulations (Sandimmune).⁴⁷⁹

Specific Populations

Pregnancy

Category C.⁴⁷⁸ ⁴⁷⁹

Lactation

Distributed into milk; women should not breast-feed infants while receiving the drug.¹ ⁷⁵ ¹⁷⁰ ³⁹¹ ⁴²⁴

Pediatric Use

No adequate and controlled studies to date; however, cyclosporine has been used in children ≥6 months of age without unusual adverse effects.¹ ¹⁷⁰ Modified oral formulations (Gengraf and Neoral) used in children ≥1 year of age.³⁹¹ ⁴⁷⁶ ⁴⁷⁷

Consider the possibility that serious nephrotoxicity, hypertension, and/or seizures may occur.⁴¹ ⁷⁴

Safety and efficacy of cyclosporine for the management of juvenile rheumatoid arthritis or psoriasis in children <18 years of age not established.⁴³¹ ⁴⁷⁶ ⁴⁷⁷

Geriatric Use

Assess renal function with particular care, due to greater frequency of decreased renal function observed in geriatric patients.⁴³¹

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.⁴³¹

Renal Impairment

Use with caution; assess renal function prior to and periodically during prolonged therapy.⁴⁷⁸ ⁴⁷⁹ Dosage adjustment may be necessary depending on degree of renal impairment.⁴⁷⁸ ⁴⁷⁹

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.¹ ¹⁷⁰ ³⁹¹

Contraindicated in rheumatoid arthritis or psoriasis patients with abnormal renal function.⁴³¹

Common Adverse Effects

Transplant recipients: Renal impairment, tremor, hirsutism, hypertension, gum hyperplasia.⁴⁷⁸ ⁴⁷⁹

Rheumatoid arthritis: Renal impairment, hypertension, headache, GI disturbances, hirsutism/hypertrichosis.⁴⁷⁸

Psoriasis: Renal impairment, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, flu-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, musculoskeletal or joint pain.⁴⁷⁸

Drug Interactions

Extensively metabolized by CYP3A.¹⁷⁰ ¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ³⁹¹ ⁴²⁴ ⁴²⁵ ⁴²⁹ ⁴³⁰

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A inhibitors: Potential pharmacokinetic interaction (increased cyclosporine concentrations in biologic fluid).¹⁷⁰ ¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ³⁹¹ ⁴²⁹ ⁴³⁰

CYP3A inducers: Potential pharmacokinetic interaction (decreased cyclosporine concentrations in biologic fluid).¹⁷⁰ ³⁹¹

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.³⁵¹ ³⁹¹ ⁵⁹⁴ ⁵⁹⁵ Use with caution.⁵⁹⁴ ⁵⁹⁵

Specific Drugs and Foods

Drug or Food	Interaction	Comments
ACE inhibitors	Possible hyperkalemia⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹	Caution advised and control of potassium concentrations recommended⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹
Allopurinol	Increased plasma or blood concentrations of cyclosporine¹⁷⁰ ¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ³⁹¹ ⁴⁰³ ⁴⁰⁴ ⁴²⁹ ⁴³⁰ ⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly¹⁷⁰ ³⁹¹ ⁵⁹⁴ ⁵⁹⁵
Amiodarone	Increased plasma or blood concentrations of cyclosporine¹⁷⁰ ¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ⁴²⁹ ⁴³⁰ ⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly¹⁷⁰ ³⁹¹ ⁵⁹⁴ ⁵⁹⁵
Aminoglycosides (gentamicin, tobramycin)	Possible additive nephrotoxic effects³³⁵ ⁵⁹⁴ ⁵⁹⁵ ³⁹¹ Possible increased risk of acute tubular necrosis in renal allograft recipients³⁰⁸ ³¹²	Use with caution⁵⁹⁴ ⁵⁹⁵ Avoid concomitant use in renal allograft recipients³⁰⁸
Amphotericin B	Possible additive nephrotoxic effects³³⁵ ⁵⁹⁴ ⁵⁹⁵	If concomitant therapy is necessary, temporarily withhold cyclosporine until trough serum cyclosporine concentration (determined by RIA) is <150 ng/mL; adjust subsequent dosage accordingly¹⁵
Angiotensin II receptor blockers	Possible hyperkalemia⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹	Caution advised and control of potassium concentrations recommended⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹
Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)	Decreased plasma or blood concentrations of cyclosporine¹⁰⁷ ¹¹⁷ ¹¹⁸ ¹¹⁹ ³⁰³ ³⁰⁸ ³³⁵ ⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Antifungals, azoles (fluconazole, itraconazole, ketoconazole, voriconazole)	Increased plasma or blood concentrations of cyclosporine¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ⁴²⁹ ⁴³⁰ ⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁵⁹⁴ ⁵⁹⁵	Carefully monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Bosentan	Decreased plasma concentrations of cyclosporine; increased plasma bosentan concentrations⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁵⁹³	Concomitant use contraindicated⁵⁹³
Bromocriptine	Increased plasma or blood concentrations of cyclosporine¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ⁴²⁹ ⁴³⁰ ⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Calcium-channel blocking agents	Diltiazem, nicardipine, verapamil: Increased plasma or blood concentrations of cyclosporine¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ⁴²⁹ ⁴³⁰ ⁵⁹⁴ ⁵⁹⁵ Nifedipine: Frequent gingival hyperplasia	Diltiazem, nicardipine, verapamil: Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Ciprofloxacin	Possible additive nephrotoxic effects⁵⁹⁴ ⁵⁹⁵	Use with caution⁵⁹⁴ ⁵⁹⁵
Colchicine	Possible additive nephrotoxic effects;⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ increased plasma or blood concentrations of cyclosporine¹⁷⁰ ¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ³⁹¹ ⁴²⁹ ⁴³⁰ Possible decreased clearance of colchicine increasing the potential for enhanced colchicine toxicity (myopathy, neuropathy)⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵ Monitor closely for colchicine toxicity; adjust colchicine dosage or discontinue drug as indicated⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹
Contraceptives, oral	Increased plasma or blood concentrations of cyclosporine⁴⁷⁸ ⁴⁷⁹	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Corticosteroids (methylprednisolone, prednisolone)	Increased plasma or blood concentrations of cyclosporine;⁷⁷ ¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ⁴²⁹ ⁴³⁰ ⁵⁹⁴ ⁵⁹⁵ possible decreased clearance of prednisolone;⁴⁷⁸ ⁴⁷⁹ seizures reported with combined cyclosporine and high-dose corticosteroid therapy¹ ¹²⁹ ¹³⁰ ¹³¹ ¹⁵³ ¹⁵⁴ ¹⁷⁰ ³³⁵ ³⁹¹	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Co-trimoxazole	Possible additive nephrotoxic effects³³⁵ ⁵⁹⁴ ⁵⁹⁵	Use with caution⁵⁹⁴ ⁵⁹⁵
Danazol	Increased plasma or blood concentrations of cyclosporine¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ³⁰³ ³⁰⁸ ³³⁴ ³⁷⁸ ³⁸⁰ ⁴²⁹ ⁴³⁰ ⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Digoxin	Possible decreased volume of distribution and clearance of digoxin;³⁰³ ³⁰⁸ ³¹⁰ ⁵⁹⁴ ⁵⁹⁵ digoxin toxicity reported ³⁰³ ³⁰⁸ ³¹⁰ ³⁷⁸ ⁵⁹⁴ ⁵⁹⁵	Monitor closely for digoxin toxicity; adjust digoxin dosage accordingly⁴⁷⁸ ⁴⁷⁹
Diuretics, potassium-sparing	Possible hyperkalemia¹ ⁴⁷⁶ ⁴⁷⁷ ⁵⁹⁴ ⁵⁹⁵	Concomitant use not recommended¹ ⁴⁷⁶ ⁴⁷⁷ ⁵⁹⁴ ⁵⁹⁵
Fibric acid derivatives	Possible additive nephrotoxic effects⁴⁷⁸ ⁴⁷⁹ ⁵⁹⁴ ⁵⁹⁵	Use with caution⁵⁹⁴ ⁵⁹⁵
Grapefruit juice	Increased oral bioavailability of cyclosporine⁴³² ⁴³⁵ ⁴³⁸ ⁴⁴² ⁴⁴⁴ ⁴⁴⁵ ⁴⁴⁶ ⁴⁴⁷ ⁴⁵³ ⁴⁵⁵ ⁴⁷⁸ ⁴⁷⁹	Avoid concomitant use⁴⁷⁸ ⁴⁷⁹
Histamine H₂-receptor antagonists (cimetidine, ranitidine)	Possible additive nephrotoxic effects³³⁵
HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir)	Possible increased plasma or blood concentrations of cyclosporine¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ⁴²⁹ ⁴³⁰ ⁵⁹⁴ ⁵⁹⁵ Avoid concomitant use	Use concomitantly with caution⁵⁹⁴ ⁵⁹⁵
HMG CoA reductase inhibitors (statins)(atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin)	Decreased clearance of the statin; possible myositis, myolysis, or rhabdomyolysis³⁰³ ³⁰⁴ ³⁰⁵ ³⁰⁷ ³³⁵ ⁵⁹⁴ ⁵⁹⁵	Reduce statin dosage; temporarily withhold or discontinue statin therapy in those with signs/symptoms of myopathy or risk factors predisposing to severe renal injury secondary to rhabdomyolysis⁵⁹⁴ ⁵⁹⁵
Imatinib	Increased plasma or blood concentrations of cyclosporine⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Immunosuppressive agents	Increased risk of lymphoma and susceptibility to infection¹ ⁹ ¹⁶ ¹⁷⁰	Avoid concomitant use of conventional (nonmodified) oral formulations or the concentrate for injection with other immunosuppressive agents (except for corticosteroids)¹ ⁹ ¹⁶ ¹⁷⁰ Modified oral formulations (Gengraf, Neoral) may be administered with other immunosuppressives, although the degree of immunosuppression produced may result in an increased risk of lymphoma and other neoplasms and in susceptibility to infection³⁹¹ ⁴⁷⁶ ⁴⁷⁷ Patients with psoriasis should not receive cyclosporine concomitantly with other immunosuppressive agents since excessive immunosuppression may result⁴³¹
Macrolides (azithromycin, clarithromycin, erythromycin)	Increased plasma or blood concentrations of cyclosporine¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ⁴²⁹ ⁴³⁰ ⁴⁷⁸ ⁴⁷⁹	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁴⁷⁸ ⁴⁷⁹
Melphalan	Possible additive nephrotoxic effects³³⁵ ⁵⁹⁴ ⁵⁹⁵	Use with caution⁵⁹⁴ ⁵⁹⁵
Metoclopramide	Increased plasma or blood concentrations of cyclosporine¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ³⁰³ ³⁷⁸ ³⁸⁰ ⁴²⁹ ⁴³⁰ ⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Methotrexate	Possible increased plasma concentrations of methotrexate and decreased plasma concentrations of 7-hydroxymethotrexate; no apparent effect on blood concentrations of cyclosporine ⁴³¹ ⁴⁷⁸ ⁴⁷⁹	Initiate cyclosporine at same initial dosage and range of adjustment as when administered alone⁴³¹ Generally administer modified formulations of cyclosporine (Gengraf, Neoral) at ≤3 mg/kg daily in patients receiving methotrexate ≤15 mg weekly⁴³¹ ⁴⁷⁶ ⁴⁷⁷
Nafcillin	Decreased plasma or blood concentrations of cyclosporine³⁰³ ³⁰⁸ ⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
NSAIAs (diclofenac, naproxen, sulindac)	Possible additive nephrotoxic effects;³³⁵ ⁵⁹⁴ ⁵⁹⁵ possible increased BP and/or serum potassium concentrations³⁰⁸ ⁴²⁰ ⁴²¹ Increased diclofenac AUC⁴³¹ ⁴⁶¹	Monitor S_cr following modification of concomitant NSAIA therapy (increase in NSAIA dosage or initiation of new NSAIA)⁴³¹ Select diclofenac dosage at lower end of the recommended dosage range⁴³¹
Octreotide	Decreased plasma or blood concentrations of cyclosporine⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Orlistat	Decreased absorption of cyclosporine⁴⁷⁸ ⁴⁷⁹	Avoid concomitant use⁴⁷⁸ ⁴⁷⁹
Potassium-sparing or -containing drugs	Possible hyperkalemia⁴⁷⁸ ⁴⁷⁹	Caution advised; control of potassium concentrations recommended⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹
Quinupristin/dalfopristin	Increased plasma or blood concentrations of cyclosporine¹⁷⁷ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁶ ⁴²⁹ ⁴³⁰ ⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Rifabutin	Possible increased metabolism of cyclosporine⁴⁷⁸ ⁴⁷⁹	Use with caution⁴⁷⁸ ⁴⁷⁹
Rifampin	Decreased plasma or blood concentrations of cyclosporine¹¹³ ¹¹⁴ ¹¹⁵ ¹¹⁶ ³³⁵ ⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
St. John’s wort	Marked decrease in blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹	Avoid concomitant use⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹
Sirolimus	Increased S_cr with concomitant sirolimus and full-dose cyclosporine therapy⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ Increased blood sirolimus concentrations with concomitant administration⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹	Increase in S_cr generally is reversible with cyclosporine dosage reduction⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹ Administer sirolimus 4 hours after cyclosporine to minimize effect on sirolimus concentrations⁴⁷⁶ ⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹
Sulfinpyrazone	Decreased plasma or blood concentrations of cyclosporine⁴⁷⁸ ⁴⁷⁹	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁴⁷⁸ ⁴⁷⁹
Tacrolimus	Possible additive nephrotoxic effects³³⁵ ⁵⁹⁴ ⁵⁹⁵	Avoid concomitant use^a
Terbinafine	Decreased plasma or blood concentrations of cyclosporine⁴⁷⁸ ⁴⁷⁹	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁴⁷⁸ ⁴⁷⁹
Ticlopidine	Decreased plasma or blood concentrations of cyclosporine³⁰³ ³⁰⁸ ³³⁵ ⁵⁹⁴ ⁵⁹⁵	Monitor concentration of cyclosporine; adjust cyclosporine dosage accordingly⁵⁹⁴ ⁵⁹⁵
Vaccines	Possible decreased immune response to vaccination⁵⁹⁴ ⁵⁹⁵	Avoid administration of live vaccines during cyclosporine therapy³³⁵ ⁵⁹⁴ ⁵⁹⁵
Vancomycin	Possible additive nephrotoxic effects³³⁵ ⁵⁹⁴ ⁵⁹⁵	Use with caution⁵⁹⁴ ⁵⁹⁵

Cyclosporine Pharmacokinetics

Absorption

Bioavailability

Variably and incompletely absorbed following oral administration.¹ ² ¹⁷⁰ ¹⁷¹ ³⁹¹ Undergoes extensive first-pass metabolism following oral administration.²

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.³⁹¹ ⁴²⁵

Peak blood and plasma concentrations are attained about 3.5 hours following oral administration of conventional (nonmodified) formulations.⁴⁷⁹

Modified oral formulations (Gengraf, Neoral) have greater bioavailability than the conventional (nonmodified) oral formulations (Sandimmune).³⁹¹ ⁴¹¹ ⁴¹² ⁴²² ⁴⁷⁶ ⁴⁷⁷ (See Bioequivalency of Formulations under Cautions.)

Conventional (nonmodified) liquid-filled capsules of Sandimmune are bioequivalent to Sandimmune oral solution.¹⁷⁰ ¹⁷¹ ¹⁷³

Modified oral capsules of Neoral are bioequivalent to Neoral oral solution.³⁹¹ ⁴⁰⁷ ⁴¹⁴ Modified oral capsules of Gengraf are bioequivalent to Gengraf oral solution.⁴⁷⁶ ⁴⁷⁷ The Neoral and Gengraf modified oral formulations are bioequivalent to each other.⁴⁸⁰ ⁴⁸¹ ⁴⁸²

Food

Data regarding effect of food on cyclosporine absorption are discordant.³⁹¹ ⁴¹⁷ ⁴²⁵

Plasma Concentrations

Possible decreased frequency of organ rejection when trough blood concentrations (determined by HPLC) are >100 ng/mL.²

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.¹

Possible association between trough serum concentrations >500 ng/mL (determined by RIA) and cyclosporine-induced nephrotoxicity.⁹

Distribution

Extent

Widely distributed into body fluids and tissues;¹ ⁸ most of drug is distributed outside the blood volume.³⁹¹

Crosses the placenta⁷⁵ ¹³⁷ ¹³⁹ ⁴²⁵ and is distributed into milk.¹ ¹³⁹ ⁴²⁵

Plasma Protein Binding

Approximately 90–98% (mainly lipoproteins).¹ ² ³⁹¹ ⁴²⁵

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.³⁹¹ ⁴²⁵

Elimination Route

Excreted principally via bile, almost entirely as metabolites; about 6% of a dose excreted in urine.¹ ¹⁷⁰ ³⁹¹ ⁴²⁵

Half-life

Biphasic; terminal half-life averages 8.4–27 hours (range: 4–50 hours).¹ ⁸ ¹⁷⁰ ³⁹¹ ⁴²⁴ ⁴²⁵

Stability

Storage

Oral

Capsules, liquid-filled (nonmodified)

25°C (may be exposed to 15–30°C).⁴⁷⁹

Oral Solution, Concentrate (nonmodified)

<30°C.⁴⁷⁹ Do not refrigerate; protect from freezing.⁴⁷⁹

Discard 2 months after opening.⁴⁷⁹

Capsules, liquid-filled (modified)

Neoral: 20–25°C.⁴⁷⁸

Gengraf: 15–30°C.⁴⁷⁶

Oral Solution (modified)

Neoral: 20–25°C.⁴⁷⁸ Do not refrigerate.⁴⁷⁸

Gengraf: 15–30°C.⁴⁷⁷ Do not refrigerate.⁴⁷⁷

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.⁴⁷⁷ ⁴⁷⁸

Discard 2 months after opening.⁴⁷⁷ ⁴⁷⁸

Parenteral

Concentrate for Injection

<30°C; protect from light.⁴⁷⁹

Polyoxyl 35 castor oil (in cyclosporine injection) can cause leaching of bis(2-ethylhexyl) phthalate (DEHP) from PVC containers.¹ Cyclosporine 2 mg/mL is stable for 24 hours in dextrose 5% or sodium chloride 0.9% in glass or PVC containers;⁹⁴ however, to minimize patient exposure to DEHP, some clinicians suggest that diluted solutions in PVC containers be administered immediately after preparation.⁹⁵

Compatibility

Parenteral

Solution CompatibilityHID

Compatible
Amino acids 5%, dextrose 25%
Dextrose 5% in water
Fat emulsion 10 and 20%, intravenous
Sodium chloride 0.9%

Drug CompatibilityHID

Admixture Compatibility
Compatible
Ciprofloxacin
Incompatible
Magnesium sulfate

Y-Site CompatibilityHID
Compatible
Anidulafungin
Caspofungin acetate
Ceftaroline fosamil
Doripenem
Linezolid
Meropenem
Micafungin sodium
Propofol
Sargramostim
Incompatible
Acyclovir sodium
Amphotericin B cholesteryl sulfate complex
Variable
Mycophenolate mofetil HCl
Telavancin HCl

Actions

Inhibits cell-mediated immune responses such as allograft rejection,¹ ² ³ delayed hypersensitivity (e.g., tuberculin-induced),¹ ² ³ experimental allergic encephalomyelitis,¹ ² ³ Freund’s adjuvant-induced arthritis,¹ and graft-vs-host disease in animal studies.¹ ²
Exact mechanism(s) of immunosuppressive action not fully elucidated; appears to mainly involve inhibition of lymphocytic proliferation and function.¹ ² ⁴ ⁶
Produces nephrotoxic effects, which generally appear to be dose dependent and reversible.¹ ⁴ (See Renal Effects under Cautions.)

Advice to Patients

Risk of hypertension and renal impairment.⁴⁷⁸ ⁴⁷⁹
Necessity of routine laboratory testing (e.g., BUN, S_cr, bilirubin, liver enzymes) for assessment of renal and hepatic function.¹ ¹⁷⁰ ³⁹¹
Increased risk of neoplasia.¹ ¹⁷⁰ ³⁹¹
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.³⁹¹
Importance of administering oral cyclosporine on a consistent schedule with regard to time of day and in relation to meals.¹⁷⁰ ¹⁷¹ ³⁹¹
Importance of following manufacturer’s instructions for dilution and administration of conventional (nonmodified) oral solution and modified oral solution.⁴⁷⁷ ⁴⁷⁸ ⁴⁷⁹
Importance of avoiding grapefruit juice during cyclosporine therapy.⁴⁷⁹
For psoriasis patients, importance of appropriate protection from the sun and avoidance of excessive solar exposure.⁴³¹
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.⁴⁷⁸ ⁴⁷⁹
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.⁴⁷⁸ ⁴⁷⁹
Importance of informing patients of other important precautionary information.⁴⁷⁸ ⁴⁷⁹ (See Cautions.)

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.

cycloSPORINE
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules, liquid-filled (nonmodified)	25 mg	SandIMMUNE	Novartis
		50 mg	SandIMMUNE	Novartis
		100 mg	SandIMMUNE	Novartis
	Capsules, liquid-filled, for emulsion (modified)	25 mg	Gengraf	Abbott
			Neoral	Novartis
		100 mg	Gengraf	Abbott
			Neoral	Novartis
	For emulsion, solution (modified)	100 mg/mL	Gengraf	Abbott
			Neoral	Novartis
	For solution, concentrate (nonmodified)	100 mg/mL	SandIMMUNE	Novartis
Parenteral	For injection, concentrate for IV infusion only	50 mg/mL	SandIMMUNE I.V.	Novartis

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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82. Schran HF. (Sandoz, Inc, East Hanover, NJ): Personal communication; 1984 Jul 2.

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90. Reviewers’ comments on Lymphocyte Immune Globulin, Antithymocyte Globulin (Equine) 92:00 (personal observations); 1985 Mar.

91. Halloran PF, Lien J, Aprile M et al. Preliminary results of a randomized comparison of cyclosporine and Minnesota antilymphoblast globulin. Transplant Proc. 1982; 14:627-30. http://www.ncbi.nlm.nih.gov/pubmed/6301117?dopt=AbstractPlus

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93. Hall BM, Tiller DJ, Horvath JS et al. Treatment of renal transplantation rejection: cyclosporin A versus conventional treatment with azathioprine, prednisone and antithymocyte immunoglobulin in primary cadaveric renal transplantation. Med J Aust. 1985; 142:179-85. http://www.ncbi.nlm.nih.gov/pubmed/3881654?dopt=AbstractPlus

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95. Venkataramanan R, Burckart GJ, Ptachcinski RJ et al. Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous cyclosporine solution. Am J Hosp Pharm. 1986; 43:2800-2. http://www.ncbi.nlm.nih.gov/pubmed/3799618?dopt=AbstractPlus

96. Canadian Multicentre Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation: analysis at three years. N Engl J Med. 1986; 314:1219-25. http://www.ncbi.nlm.nih.gov/pubmed/2871486?dopt=AbstractPlus

97. Deeg HJ, Storb R, Thomas ED et al. Cyclosporine as prophylaxis for graft-versus-host disease: a randomized study in patients undergoing marrow transplantation for acute nonlymphoblastic leukemia. Blood. 1985; 65:1325-34. http://www.ncbi.nlm.nih.gov/pubmed/3888312?dopt=AbstractPlus

98. Storb R, Deeg HJ, Thomas ED et al. Marrow transplantation for chronic myelocytic leukemia: a controlled trial of cyclosporine versus methotrexate for prophylaxis of graft-versus-host disease. Blood. 1985; 66:698-702. http://www.ncbi.nlm.nih.gov/pubmed/2862933?dopt=AbstractPlus

99. Irle C, Deeg HJ, Buckner CD et al. Marrow transplantation for leukemia following fractionated total body irradiation: a comparative trial of methotrexate and cyclosporine. Leuk Res. 1985; 9:1255-61. http://www.ncbi.nlm.nih.gov/pubmed/3906282?dopt=AbstractPlus

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