Cyclosporine

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

• 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

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 cyclosporine^{1 170} 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 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

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 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

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 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

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 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 hyperkalemia^{2 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.