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Cyclosporine

Class: Immunosuppressive Agents
VA Class: IM600
Chemical Name: Cyclosporin A
Molecular Formula: C62H111N11O12
CAS Number: 59865-13-3
Brands: Gengraf, Neoral, SandIMMUNE

Medically reviewed on Jun 19, 2018

Warning

    Supervising Clinician and Medical Resources
  • 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

    Effects of Immunosuppression
  • 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

    Bioequivalency of Formulations
  • 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.)

    Psoriasis Patients
  • 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

See also: Dupixent

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.2 19 25 26 97 98 99 100

Has been used for the treatment of moderate to severe, acute graft-vs-host disease 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 and other DMARDs.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.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 Scr twice for a baseline.431 464

  • Monitor BP and Scr every 2 weeks during the first 3 months of therapy; thereafter, monitor BP and Scr monthly in stable patients.431 Always monitor Scr 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 Scr (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 Scr 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 Scr 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
IV

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

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

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

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 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

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 Scr 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
IV

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 Scr <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
IV

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 Scr 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 Scr before adjusting cyclosporine dosage; these increases do not necessarily indicate the occurrence of organ rejection.1 170 391 If elevations of BUN and Scr 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 Scr 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 Scr 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

Interactions for Cyclosporine

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 Scr 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 Scr with concomitant sirolimus and full-dose cyclosporine therapy476 477 478 479

Increased blood sirolimus concentrations with concomitant administration476 477 478 479

Increase in Scr 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 usea

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

For information on systemic interactions resulting from concomitant use, see Interactions.

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, Scr, 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.)

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

AHFS DI Essentials. © Copyright 2018, Selected Revisions June 19, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

References

1. Sandoz Pharmaceuticals Corporation. Sandimmune (cyclosporine) oral solution and I.V. prescribing information. East Hanover, NJ; 1988 Apr 1.

2. Canafax DM, Ascher NL. Cyclosporine immunosuppression. Clin Pharm. 1983; 2:515-24. http://www.ncbi.nlm.nih.gov/pubmed/6360494?dopt=AbstractPlus

3. White DJG. Cyclosporin A—clinical pharmacology and therapeutic potential. Drugs. 1982; 24:322-34. http://www.ncbi.nlm.nih.gov/pubmed/6754333?dopt=AbstractPlus

4. Sheil AGR. Cyclosporin A—a new immune suppressive agent. Med J Aust. 1982; 1:37-9. http://www.ncbi.nlm.nih.gov/pubmed/7038415?dopt=AbstractPlus

5. Sandoz, Inc. Sandimmune pharmacy fact sheet. East Hanover, NJ; 1983 Nov. SDI DD-4.

6. Borel JF, Feurer C, Magnée C et al. Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology. 1977; 32:1017-25. http://www.ncbi.nlm.nih.gov/pubmed/328380?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1445439&blobtype=pdf

7. Shulman H, Striker G, Deeg HJ et al. Nephrotoxicity of cyclosporin A after allogeneic marrow transplantation. N Engl J Med. 1981; 305:1392-5. http://www.ncbi.nlm.nih.gov/pubmed/7029278?dopt=AbstractPlus

8. Beveridge T, Gratwohl A, Michot F et al. Cyclosporin A: pharmacokinetics after a single dose in man and serum levels after multiple dosing in recipients of allogeneic bone-marrow grafts. Curr Ther Res. 1981; 30:5-18.

9. Merion RM, White DJG, Thiru S et al. Cyclosporine: five years’ experience in cadaveric renal transplantation. N Engl J Med. 1984; 310:148-54. http://www.ncbi.nlm.nih.gov/pubmed/6361559?dopt=AbstractPlus

10. Burckart GJ. Monitoring cyclosporine therapy. Clin Pharm. 1983; 2:568. http://www.ncbi.nlm.nih.gov/pubmed/6653058?dopt=AbstractPlus

11. European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet. 1983; 2:986-9. http://www.ncbi.nlm.nih.gov/pubmed/6138592?dopt=AbstractPlus

12. White DJG, McNaughton D, Calne RY. Is the monitoring of cyclosporin-A serum levels of clinical value? Transplant Proc. 1983; 15:454-6.

13. Ferguson RM, Sutherland DER, Simmons RL et al. Ketoconazole, cyclosporin metabolism, and renal transplantation. Lancet. 1982; 2:882-3. http://www.ncbi.nlm.nih.gov/pubmed/6126744?dopt=AbstractPlus

14. Dieperink H, Moller J. Ketoconazole and cyclosporin. Lancet. 1982; 2:1217. http://www.ncbi.nlm.nih.gov/pubmed/6128518?dopt=AbstractPlus

15. Kennedy MS, Deeg HJ, Siegel M et al. Acute renal toxicity with combined use of amphotericin B and cyclosporine after marrow transplantation. Transplantation. 1983; 35:211-5. http://www.ncbi.nlm.nih.gov/pubmed/6340275?dopt=AbstractPlus

16. Canadian Multicentre Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med. 1983; 309:809-15. http://www.ncbi.nlm.nih.gov/pubmed/6350878?dopt=AbstractPlus

17. Anon. Cyclosporine—a new immunosuppressive agent. Med Letter Drugs Ther. 1983; 25:77-8.

18. Beveridge T. Cyclosporin-A: an evaluation of clinical results. Transplant Proc. 1983; 15:433-7.

19. Barrett AJ, Kendra JR, Lucas CF et al. Cyclosporin A as prophylaxis against graft-versus-host disease in 36 patients. BMJ. 1982; 285:162-6. http://www.ncbi.nlm.nih.gov/pubmed/6807391?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1499317&blobtype=pdf

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21. Bird AG, McLachlan SM. Cyclosporin A and Epstein-Barr virus. Lancet. 1980; 2:418. http://www.ncbi.nlm.nih.gov/pubmed/6105533?dopt=AbstractPlus

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23. Calne RY, Williams R, Lindop M et al. Improved survival after orthotopic liver grafting. BMJ. 1981; 283:115-8. http://www.ncbi.nlm.nih.gov/pubmed/6789932?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1506064&blobtype=pdf

24. Powles RL, Barrett AJ, Clink H et al. Cyclosporin A for the treatment of graft-versus-host disease in man. Lancet. 1978; 2:1327-31. http://www.ncbi.nlm.nih.gov/pubmed/82837?dopt=AbstractPlus

25. Powles RL, Clink HM, Spence D et al. Cyclosporin A to prevent graft-versus-host disease in man after allogeneic bone-marrow transplantation. Lancet. 1980; 1:327-9. http://www.ncbi.nlm.nih.gov/pubmed/6101787?dopt=AbstractPlus

26. Gale RP, Kay HEM, Rimm AA et al. Bone-marrow transplantation for acute leukaemia in first remission. Lancet. 1982; 2:1006-9. http://www.ncbi.nlm.nih.gov/pubmed/6127500?dopt=AbstractPlus

27. Stiller CR, Laupacis A, Dupre J et al. Cyclosporine for treatment of early type I diabetes: preliminary results. N Engl J Med. 1983; 308:1226-7. http://www.ncbi.nlm.nih.gov/pubmed/6341839?dopt=AbstractPlus

28. Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med. 1979; 301:555. http://www.ncbi.nlm.nih.gov/pubmed/460314?dopt=AbstractPlus

29. Calne RY, Rolles K, White DJG et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979; 2:1033-6. http://www.ncbi.nlm.nih.gov/pubmed/91781?dopt=AbstractPlus

30. Siegl H, Ryffel B. Effect of cyclosporin on renin-angiotensin-aldosterone system. Lancet. 1982; 2:1274. http://www.ncbi.nlm.nih.gov/pubmed/6128567?dopt=AbstractPlus

31. Windholz M, ed. The Merck index. 10th ed. Rahway, NJ: Merck & Co, Inc; 1983:396.

32. Thommen-Scott K. Antimalarial activity of cyclosporin A. Agents Actions. 1981; 11:770-3. http://www.ncbi.nlm.nih.gov/pubmed/7041571?dopt=AbstractPlus

33. Kreis W, Soricelli A. Cyclosporins: immunosuppressive agents with antitumor activity. Experientia. 1979; 35:1506-8. http://www.ncbi.nlm.nih.gov/pubmed/510504?dopt=AbstractPlus

34. Bueding E, Hawkins J, Cha YN. Antischistosomal effects of cyclosporin A. Agents Actions. 1981; 11:380-3. http://www.ncbi.nlm.nih.gov/pubmed/7282489?dopt=AbstractPlus

35. Starzl TE, Iwatsuki S, Van Thiel DH et al. Evolution of liver transplantation. Hepatology. 1982; 2:614-36. http://www.ncbi.nlm.nih.gov/pubmed/6749635?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2972731&blobtype=pdf

36. Oyer PE, Stinson EB, Jamieson SW et al. Cyclosporine in cardiac transplantation: a 2½ year follow-up. Transplant Proc. 1983; 15(Suppl 1):2546-52. http://www.ncbi.nlm.nih.gov/pubmed/6420962?dopt=AbstractPlus

37. Davison AN, Ilyas AA. Cyclosporin A inhibits ganglioside-stimulated lymphocyte rosette formation in multiple sclerosis. Int Arch Allergy Appl Immunol. 1982; 69:393-6. http://www.ncbi.nlm.nih.gov/pubmed/7141720?dopt=AbstractPlus

38. Nussenblatt RB, Palestine AG, Rook AH et al. Treatment of intraocular inflammatory disease with cyclosporin A. Lancet. 1983; 2:235-8. http://www.ncbi.nlm.nih.gov/pubmed/6135075?dopt=AbstractPlus

39. Klintmalm G, Bergstrand A, Ringden O et al. Graft biopsy for the differentiation between nephrotoxicity and rejection in cyclosporin-A-treated renal transplant recipients. Transplant Proc. 1983; 15:493-6.

40. Starzl TE, Iwatsuki S, Malatack JJ et al. Liver and kidney transplantation in children receiving cyclosporin A and steroids. J Pediatr. 1982; 100:681-6. http://www.ncbi.nlm.nih.gov/pubmed/6802949?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3035841&blobtype=pdf

41. Conley SB, Brewer ED, Flechner SM et al. Renal transplantation using cyclosporine in pediatric patients 3 to 17 years old. Transplant Proc. 1983; 15(Suppl 1):2528-30.

42. Thiru S, Calne RY, Nagington J. Lymphoma in renal allograft patients treated with cyclosporin-A as one of the immunosuppressive agents. Transplant Proc. 1981; 13:359-64. http://www.ncbi.nlm.nih.gov/pubmed/7022852?dopt=AbstractPlus

43. Starzl TE, Nalesnik MA, Porter KA et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet. 1984; 1:583-7. http://www.ncbi.nlm.nih.gov/pubmed/6142304?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2987704&blobtype=pdf

44. Nickell SP, Scheibel LW, Cole GA. Inhibition by cyclosporin A of rodent malaria in vivo and human malaria in vitro. Infect Immun. 1982; 37:1093-100. http://www.ncbi.nlm.nih.gov/pubmed/6752020?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=347653&blobtype=pdf

45. Stiller C, Canadian Transplant Study Group. The requirements for maintenance steroids in cyclosporine-treated renal transplant recipients. Transplant Proc. 1983; 15(Suppl 1):2490-4.

46. Robinson WT, Schran HF, Barry EP. Methods to measure cyclosporine levels—high pressure liquid chromatography, radioimmunoassay, and correlation. Transplant Proc. 1983; 15(Suppl 1):2403-8.

47. Follath F, Wenk M, Vozeh S et al. Intravenous cyclosporine kinetics in renal failure. Clin Pharmacol Ther. 1983; 34:638-43. http://www.ncbi.nlm.nih.gov/pubmed/6627824?dopt=AbstractPlus

48. Stiller CR, Dupré J, Gent M et al. Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science. 1984; 223:1362-7. http://www.ncbi.nlm.nih.gov/pubmed/6367043?dopt=AbstractPlus

49. Kahan BD, Wideman CA, Flechner S et al. Anaphylactic reaction to intravenous cyclosporin. Lancet. 1984; 1:52. http://www.ncbi.nlm.nih.gov/pubmed/6140379?dopt=AbstractPlus

50. Malatack JJ, Zitelli BJ, Gartner JC et al. Pediatric liver transplantation under therapy with cyclosporin-A and steroids. Transplant Proc. 1983; 15:1292-6. http://www.ncbi.nlm.nih.gov/pubmed/21151785?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3000045&blobtype=pdf

51. Lorenz W, Schmal A, Schult H et al. Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: analysis of various components in Cremophor EL and development of a compound with reduced toxicity. Agents Actions. 1982; 12:64-80. http://www.ncbi.nlm.nih.gov/pubmed/6177219?dopt=AbstractPlus

52. Schmutzler W, Raemsch KD, Van Wersch J et al. Allergic and pseudo-allergic reactions to micelle-forming agents: developing laboratory models to determine undesired drug effects. Allergologie. 1982; 5:208-15.

53. Moneret-Vautrin DA, Laxenaire MC, Viry-Babel F. Anaphylaxis caused by anti-Cremophor EL IgG STS antibodies in a case of reaction to Althesin. Br J Anaesth. 1983; 55:469-71. http://www.ncbi.nlm.nih.gov/pubmed/6849729?dopt=AbstractPlus

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