Cyclosporine (Systemic)

[Section Outline]

Administration
Dosage

Administration

Cyclosporine is administered orally as conventional (nonmodified) or modified formulations; the drug also is administered by IV infusion.1,391,476,477

Oral Administration

Cyclosporine may be administered orally as the conventional liquid-filled capsules or the conventional oral solution.170,171 Alternatively, the drug may be administered orally as modified, liquid formulations (Gengraf^®, Neoral^®) that form emulsions in aqueous fluids; the modified formulations are available as oral solutions for emulsion and as oral liquid-filled capsules.391,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422,476,477,478,483 When exposed to an aqueous environment, Neoral^® oral solution forms a homogenous transparent emulsion with a droplet size smaller than 100 nm in diameter,423 which has been referred to as a microemulsion.391,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422 Gengraf^® also is described as forming a microemulsion when exposed to an aqueous environment.483 The 2 commercially available modified oral formulations of cyclosporine, Neoral^® and Gengraf^®, have been demonstrated to be bioequivalent to each other.480,481,482

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, and therefore the conventional (nonmodified) and modified formulations are not bioequivalent and cannot be used interchangeably without appropriate medical supervision.476,477,478,479 Patients should be informed that any change in the formulation of cyclosporine that they are receiving should be performed under the supervision of a clinician since adjustment of the dosage may be necessary and caution should be observed during such a transition.476,477,478,479

Patients should be advised that oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and in relation to meals.170,171,391,476,477 When an oral solution formulation is used, doses of cyclosporine should be measured carefully.2,391 A graduated oral syringe is provided for proper measurement of a dose of cyclosporine oral solution formulations.1,391,477 When measuring a dose of an oral solution formulation, the protective cover of the oral syringe should be removed, if present, and the prescribed dose of the drug withdrawn from the bottle of oral solution and transferred to a glass (not plastic) container of suitable beverage to enhance palatability.1,107,391,477 To increase the palatability of the conventional (nonmodified) oral solution, the measured dose of cyclosporine may be mixed with milk, chocolate milk, or orange juice, preferably at room temperature but not hot.1,107 To increase palatability of the modified oral solution of Gengraf^® or Neoral^®, the measured dose of the oral cyclosporine solution preferably should be mixed with orange or apple juice at room temperature;391,477,478 milk should not be used for dilution of the solution since the resultant mixture can be unpalatable.391,477,478 The manufacturers recommend that frequent changing of the diluting beverage be avoided.477,478,479 The diluted solution or emulsion containing cyclosporine should be stirred well and administered immediately, not allowing the mixture to stand before administration.477,478,479 Use of a glass container may minimize adherence of the drug to the walls of the container;2,477,478 styrofoam containers should not be used because they are porous and may absorb the drug.107,170,391 After the initial diluted solution or emulsion has been administered, the container should be rinsed with additional diluent (e.g., juice) and the remaining mixture administered to ensure that the entire dose of the drug has been given.1,107,391,477 After use of Neoral^® oral solution, the manufacturer states that the outside of the dosing syringe should be dried with a clean, dry towel and the syringe replaced in its protective cover.1,107,391 After use of Gengraf^® oral solution, the manufacturer states that the outside of the dosing syringe should be dried with a clean, dry towel and the syringe stored in a clean, dry place.477 To avoid turbidity, the dosing syringes for Gengraf^® and Neoral^® oral solution should not be rinsed with water, alcohol, or other cleaning agents.1,107,477 If the syringes require cleaning, they must be completely dry before reuse.170,391,477 Introduction of water into the product by any means will cause variation in dose.170

Concomitant oral administration of cyclosporine conventional (nonmodified) or modified capsules or solutions with grapefruit juice should be avoided since unpredictable but potentially clinically important increases in oral bioavailability of the drug can result.192,193,194,195,476,477 Although some evidence suggested that patients who wished to continue consumption of grapefruit juice during cyclosporine therapy could do so if at least 90 minutes elapsed between administration of the drug and such consumption,179,181 other evidence indicates that such separation in timing may not be adequate,66,199 and additional study is needed.66

IV Infusion

Because of the risk of anaphylaxis, IV administration of cyclosporine should be reserved for patients in whom oral administration of the drug is not tolerated or is contraindicated.1,170 Cyclosporine concentrate for injection must be diluted prior to IV infusion .1,170 For IV infusion, each mL of the concentrate should be diluted in 20-100 mL of 0.9% sodium chloride or 5% dextrose injection immediately before administration.1,170 Diluted solutions that have not been administered within 24 hours should be discarded.170 The required dose of diluted solution is infused over 2-6 hours.1,170

Cyclosporine concentrate for injection and the diluted solution for infusion should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1,170

Dosage

Transplant Recipients

Dosage of cyclosporine should be individualized.2,9,170,391,424,425 Monitoring blood or plasma, but preferably whole blood, concentrations of cyclosporine has an essential role in individualizing dosage and managing transplant recipients during therapy with the drug.391,424 However, optimum concentrations have not been precisely defined, and suggested ranges vary depending on the assay method and body fluid employed as well as the patient population treated and therapeutic regimen used.424 Therefore, the type of assay used, organ transplanted, time since transplantation, other immunosuppressive agents administered concurrently, and other factors are important considerations in the assessment of cyclosporine blood concentrations.391,424 The clinical evaluation of rejection and toxicity, adjustment of dosage, and assessment of compliance may be assisted by monitoring blood concentrations of cyclosporine; however, recommended ranges of cyclosporine concentrations that are consistent with optimum efficacy for all patients currently cannot be defined.391,424 Therefore, it is preferable that patients be managed using a center experienced in the use and interpretation of cyclosporine concentrations and their application to dosage adjustment.424

Laboratory Monitoring

Most clinicians currently base monitoring on trough (predose) concentrations of the drug.391,424 It is important that the sampling time for a given patient be standardized and that consideration be given to the effect of once- versus twice-daily dosing of cyclosporine.424 While most recent experience has been with assays that are specific for unchanged cyclosporine,391,424 data are accumulating on the use of total drug (both cyclosporine and metabolites) concentrations, and some centers may have switched to such monitoring methods.424 The frequency of monitoring depends in part on the time that has elapsed since transplantation, intercurrent illness, and concomitant drugs.424 While there are no hard and fast rules, and monitoring should be performed whenever clinical manifestations suggest that dosage adjustment might be necessary, some clinicians generally monitor frequently (e.g., 3 or 4 times weekly to daily) during the early posttransplantation period, reducing monitoring to once monthly by 6 months to 1 year after transplantation.9,424 Timing of determinations also should take into account the time to pharmacokinetic reequilibration following recent dosage changes; in general, determinations made within 3 days of a dosage change (2 days for children) will not reflect steady state.424 If management with a center experienced in therapeutic drug monitoring of cyclosporine is not possible, specialized references can be consulted for general monitoring and dosing guidelines.424 Results obtained with various methods are not interchangeable, and specialized references and/or the assay manufacturer's labeling should be consulted for interpretative guidelines.170,391,424

If plasma assay methods are used, the possibility that concentrations may vary with temperature at the time of plasma separation from whole blood and that cyclosporine plasma concentrations may be about 20-50% of cyclosporine blood concentrations should be considered. In addition, monitoring of blood or plasma cyclosporine concentrations does not obviate monitoring of renal function (e.g., serum creatinine and creatinine clearance determination) or tissue biopsies in patients receiving the drug.1 Periodic determination of blood or plasma cyclosporine concentrations and adjustment in dosage, when necessary, are especially important in patients, particularly hepatic allograft recipients,424 receiving long-term oral therapy since absorption of the drug may be erratic.1,170

In one suggested regimen employing a highly specific assay (high-pressure liquid chromatography [HPLC]), dosage of cyclosporine in renal allograft recipients was adjusted to achieve trough blood concentrations determined just prior to the next dose (24 hours after the previous dose) of 100-200 ng/mL.170 Blood concentrations determined by HPLC are unchanged cyclosporine alone, and they have been shown to correlate directly to those determined by monoclonal specific radioimmunoassays (m-RIA-sp).170 Nonspecific assay methods that detect both unchanged drug and its metabolites also are available,170 and such assay methods generally were employed in older studies; blood cyclosporine concentrations determined by these methods were about twice those reported with specific assay methods.170 Therefore, comparing concentrations reported in the published literature with those for a given patient using current assays must employ a detailed knowledge of the assay method used.391,424 Although several assays and assay matrices are available, the current consensus is that assays specific for unchanged cyclosporine correlate best with clinical events.391,424 Such assays include HPLC, monoclonal antibody RIAs, monoclonal antibody FPIA, and EMIT, which have sensitivity and are reproducible and convenient.391,424

Usual Dosage

For prevention of allograft rejection in adults and children, the usual initial oral dose of conventional (nonmodified) formulations of cyclosporine is 15 mg/kg administered as a single dose 4-12 hours before transplantation.1,9,479 Although this initial dose varied from 14-18 mg/kg in most clinical studies, the highest dose continues to be used in only a few transplant centers, while doses at the lower end of the range have been favored.170 Administration of even lower initial dosages (e.g., 10-14 mg/kg daily) is the trend for renal allotransplantation.170 Postoperatively, the usual dosage of 15 mg/kg (range: 14-18 mg/kg) daily, administered as a single daily dose, is continued for 1-2 weeks and then tapered by 5% per week (over about 6-8 weeks) to a maintenance dosage of 5-10 mg/kg daily.1,9,170 In several studies, pediatric patients have required and tolerated higher dosages.1,170 Some clinicians have successfully tapered maintenance dosage to as low as 3 mg/kg daily in selected renal allograft recipients without an apparent increase in graft rejection rate.1,133,170

Therapy with modified oral cyclosporine formulations (Gengraf^®, Neoral^®) can be started with an initial dose given 4-12 hours before transplantation or postoperatively.391,476,477 The initial dosage of the modified formulations varies depending on the organ transplanted and the other immunosuppressive agents included in the immunosuppressive protocol.391,476,477 Newly transplanted patients may receive a modified oral formulation at the same initial dose as for the conventional (nonmodified) oral formulation.391,476,477 A survey conducted in 1994 on the use of the conventional oral formulation in American transplant centers provides additional information on suggested initial dosages.391,476,477 Renal allograft recipients received an average initial dosage of 9 mg/kg in 2 equally divided doses daily at 75 centers.391,476,477 Hepatic allograft recipients received an average initial dosage of 8 mg/kg in 2 equally divided doses daily at 30 centers,391,476,477 and cardiac allograft recipients received an average initial dosage of 7 mg/kg in 2 equally divided doses daily at 24 centers.391,476,477 The dosage of the modified oral formulation subsequently is adjusted to attain a predefined blood cyclosporine concentration.391,476,477 The therapeutic range of trough blood concentrations of cyclosporine is the same for both the modified oral formulations and the conventional oral formulations.391,476,477 However, attainment of therapeutic trough blood concentrations of cyclosporine with the modified oral formulations will result in greater exposure (AUC) to the drug than would occur with conventional oral formulations.391,476,477 Titration of dosage should be based on clinical evaluation of rejection and patient tolerability.391,476,477 Lower maintenance dosages may be possible with the modified oral formulations.391,476,477

If consideration is given to conversion of an allograft recipient from a conventional oral formulation of cyclosporine to a modified oral one, therapy with the modified oral formulation should be initiated at the same dosage that the patient is receiving of the conventional oral formulation (1:1 conversion).391,476,477 After conversion to the modified oral formulation, the increase in trough blood concentrations may be more pronounced and clinically important in some patients.391,476,477 The initial dosage subsequently should be adjusted to attain trough blood concentrations that are similar to those achieved with the conventional oral formulation.391,476,477 However, attainment of therapeutic trough blood concentrations will result in greater exposure (AUC) to cyclosporine than would occur with the conventional oral formulation.391,476,477 Monitoring of trough blood cyclosporine concentrations every 4-7 days after conversion to the modified oral formulation is recommended strongly until this measure is the same as it was with the conventional oral formulation.391,476,477 Safety of the patient also should be monitored with evaluation of such measures as the serum creatinine concentration and blood pressure every 2 weeks for the first 2 months after conversion to the modified oral formulation.391,476,477 The dosage must be adjusted appropriately if trough blood concentrations are outside of the range desired and/or if the measures of safety worsen.391,476,477

Different strategies in dosage with the modified oral formulations are required for patients suspected of having poor absorption of cyclosporine from the conventional oral formulation.391,476,477 When trough blood concentrations are lower than expected relative to the dosage of the conventional oral formulation, the patient may have poor or inconsistent absorption of cyclosporine from this formulation.391,476,477 Patients tend to have higher blood cyclosporine concentrations after conversion to the modified oral formulations.391,476,477 The higher bioavailability of cyclosporine from the modified oral formulations may result in excessive trough blood concentrations after conversion to these formulations.391,476,477 Clinicians should be particularly cautious with conversional dosages exceeding 10 mg/kg daily.391,476,477 Individual titration of the dosage should be guided by trough blood concentrations, tolerability, and clinical response.391,476,477 After conversion to the modified oral formulation in patients who may have poor absorption of cyclosporine from the conventional oral formulation, trough blood concentrations should be measured more frequently, at least twice weekly, while such monitoring should be done daily in patients receiving more than 10 mg/kg daily, until the trough blood cyclosporine concentration is maintained in the desired range.391,476,477

In patients unable to take the drug orally, cyclosporine may be administered by IV infusion at about one-third the recommended oral dosage.1,170 The usual initial IV dose of cyclosporine for adults and children is 5-6 mg/kg administered as a single dose 4-12 hours before transplantation.1,170 Postoperatively, the usual IV dosage of 5-6 mg/kg once daily is continued until the patient is able to tolerate oral administration of the drug.1,170 Pediatric patients may require higher dosages.170 Patients should be switched to an oral formulation of cyclosporine as soon as possible after surgery.1,170

Concomitant Corticosteroid Therapy

For the prevention of allograft rejection, the manufacturer states that corticosteroid therapy should always be used concomitantly with IV cyclosporine.1,170 For the prevention of allograft rejection, the manufacturers recommend that corticosteroid therapy be administered concomitantly with conventional (nonmodified) oral formulations170 and be administered concomitantly, at least initially, with the modified oral formulations.391,476,477 Dosage of corticosteroids should be adjusted individually according to the clinical situation.1,170,391,476,477 Various schedules to taper corticosteroid dosage appear to yield similar results.170,391,476,477 Prednisone may be administered orally at an initial dosage of 2 mg/kg daily for 4 days and then tapered to 1 mg/kg daily by day 7, to 0.6 mg/kg daily by day 14, to 0.3 mg/kg daily by the end of the first month, and to a maintenance dosage of 0.15 mg/kg daily by the end of the second month.1,170,476,477 Corticosteroid dosage may be tapered further based on individual consideration of patient status and allograft function.391,476,477 Alternatively, an initial oral prednisone dose of 200 mg may be given and then tapered by 40 mg daily until a maintenance dosage of 20 mg daily is achieved; this maintenance dosage is then continued for 60 days and tapered to 10 mg daily during subsequent months.1,170

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 Some clinicians suggest that if an acute rejection episode occurs in renal allograft recipients, 1 g of methylprednisolone be administered IV daily for 3 days; this dosage may be continued for an additional 3 days if rejection does not resolve following the initial course.9 If rejection continues after two 3-day courses of therapy, switching the patient to therapy with azathioprine and corticosteroids should be considered.9 Alternatively, some clinicians suggest that methylprednisolone be administered IV in a dosage of 0.5 or 1 g daily for 3 days for the management of an acute rejection reaction in renal allograft recipients.11,22 If necessary, courses of methylprednisolone therapy may be repeated until a total dosage of 6 g has been administered.11,22 If rejection continues, cyclosporine should be discontinued and switching the patient to therapy with azathioprine and corticosteroids should be considered.11,22,70

Rheumatoid Arthritis

For the management of rheumatoid arthritis in adults and children 18 years of age and older, the usual initial dosage of a modified oral cyclosporine formulation (e.g., Gengraf^®, Neoral^®) is 2.5 mg/kg daily given in 2 divided doses.431,476,477 Therapeutic response in patients with rheumatoid arthritis generally is apparent after 4-8 weeks of therapy.431,476,477 In patients with insufficient therapeutic response who have good tolerance to the drug (including serum creatinine concentration less than 30% above baseline), the dosage may be increased by 0.5-0.75 mg/kg daily after 8 weeks and, again, after 12 weeks to a maximum of 4 mg/kg daily.431,476,477 Lack of benefit by the 16th week of therapy should be considered a therapeutic failure and cyclosporine should be discontinued.431,476,477 Therapy with salicylates, other nonsteroidal anti-inflammatory agents (NSAIAs), or oral corticosteroids may be continued during cyclosporine therapy.431,476,477 To control adverse effects (e.g., hypertension, elevations in serum creatinine concentration to 30% above baseline, clinically important laboratory test abnormalities) that occur at any time during cyclosporine therapy, the cyclosporine dosage should be decreased by 25-50%.431,476,477 Cyclosporine should be discontinued if adverse effects are severe or do not respond to reduction of dosage.431,476,477

When cyclosporine is used concomitantly with methotrexate for the management of rheumatoid arthritis, cyclosporine should be administered at the same initial dosage and range of adjustment as when administered alone.431,476,477 Administration of a modified oral cyclosporine formulation at 3 mg/kg daily or less generally is applicable in patients also receiving methotrexate at up to 15 mg weekly.431,476,477 There currently is only limited experience with long-term treatment of rheumatoid arthritis with the modified oral cyclosporine formulations.431,476,477 Following discontinuance of the drug, control of rheumatoid arthritis usually wanes within 4 weeks.431,476,477

Use of cyclosporine for rheumatoid arthritis should be preceded by careful physical examination of the patient, including measurement of blood pressure on at least 2 occasions and determination of serum creatinine concentration twice for a baseline.431,464,476,477 During the first 3 months of therapy with cyclosporine, blood pressure and serum creatinine concentration should be evaluated every 2 weeks; thereafter, patients should be evaluated monthly if they are stable.431,476,477 Hypertension that develops during therapy with cyclosporine should elicit reduction of the dosage by 25-50%.431,476,477 Persistent hypertension should be managed by further reduction of the dosage of cyclosporine or use of antihypertensive agents.431,476,477 Withdrawal of cyclosporine generally results in return of blood pressure to baseline.431,476,477 Serum creatinine concentration and blood pressure should always be monitored after concomitant NSAIA therapy is modified by an increase in dosage and after initiation of new NSAIA therapy during cyclosporine therapy.431,476,477 Monthly evaluation with complete blood cell count and liver function tests is recommended in patients who also are receiving methotrexate concomitantly with cyclosporine.431,476,477

Psoriasis

For the management of psoriasis in adults and children 18 years of age and older, the usual initial dosage of a modified oral cyclosporine formulation (e.g., Gengraf^®, Neoral^®) is 1.25 mg/kg twice daily.431,458,476,477 This dosage should be continued for at least 4 weeks unless prohibited by adverse effects.431,476,477 Some improvement in clinical manifestations of psoriasis generally is observed after 2 weeks of therapy.431,476,477 If the initial cyclosporine dosage does not produce substantial clinical improvement within 4 weeks, dosage should be increased by approximately 0.5 mg/kg daily once every 2 weeks.431,476,477 Dosage may be increased in these increments to a maximum of 4 mg/kg daily based on the patient's tolerance and response.431,476,477

Cyclosporine may not produce satisfactory control and stabilization of psoriasis until after 12-16 weeks of therapy.476,477,478 In a clinical study that evaluated titration of the dosage of cyclosporine, improvement of psoriasis by at least 75%, as indicated by scores on the Psoriasis Area and Severity Index, was observed in 51 or 79% of patients after 8 or 16 weeks of therapy, respectively.476,477,478 Lack of satisfactory response after patients receive 6 weeks of cyclosporine at the maximum dosage tolerated, up to 4 mg/kg daily, should lead to discontinuance of therapy.476,477,478

In patients whose disease is controlled adequately and who appear stable, the regimen of cyclosporine should be adjusted so that the patient receives the lowest dosage that maintains an adequate response, which would not necessarily be total clearance of psoriasis.431,458,476,477 A satisfactory response was maintained in 60% of patients in clinical studies with dosages at the lower end of the recommended range.431,476,477 Dosages less than 2.5 mg/kg daily also may be equally effective.476,477,478

To control adverse effects (e.g., hypertension, elevations in serum creatinine concentration to 25% or more above baseline, clinically important laboratory test abnormalities) that occur at any time during cyclosporine therapy, the dosage should be decreased by 25-50%.431,476,477 Cyclosporine should be discontinued if adverse effects are severe or do not respond to reduction of the dosage.431,476,477

Discontinuance of cyclosporine therapy will result in relapse after several weeks, with approximately 50 or 75% of patients experiencing relapse within 6 or 16 weeks of discontinuance, respectively.431,476,477 Rebound does not occur in most patients after withdrawal of cyclosporine.431,476,477 Transformation of chronic plaque psoriasis to more severe forms of psoriasis that included pustular and erythrodermic psoriasis reportedly has occurred in some patients.431,476,477 There currently is only limited experience with the long-term treatment of psoriasis with modified oral cyclosporine formulations, and the manufacturers do not recommend continuous therapy with the drug for extended periods exceeding 1 year.431,476,477 Strategies in the long-term management of psoriasis should include consideration of alternation of cyclosporine with other therapies.431,476,477

Use of cyclosporine for psoriasis should be preceded by careful dermatologic and physical examination of the patient, including measurement of blood pressure on at least 2 occasions.431,458,476,477 Physical examination should include evaluation for the presence of occult infection because cyclosporine is an immunosuppressive agent.431,476,477 The patient also should be evaluated for the presence of tumors at this initial examination and throughout therapy with cyclosporine.431,476,477 A biopsy should be obtained from dermatologic lesions that do not typify psoriasis before therapy with cyclosporine commences.431,476,477 Cyclosporine should be administered only after malignant or premalignant dermatologic lesions have been treated appropriately and only if other therapies for psoriasis are not an option.431,476,477

During the first 3 months of therapy with cyclosporine in the management of psoriasis, blood pressure should be evaluated every 2 weeks; thereafter, patients should be evaluated monthly if they are stable or more frequently if their dosage is adjusted.431,476,477 Hypertension may occur at recommended dosages, with risk increased as the dosage and duration of therapy with the drug increases.431,476,477 If hypertension develops during therapy with cyclosporine, dosage should be reduced by 25-50% in patients without a history of hypertension prior to receiving the drug.431,476,477 Cyclosporine should be withdrawn if hypertension fails to respond to multiple reductions in dosage.431,476,477 Antihypertensive therapy of patients being managed for hypertension prior to initiation of cyclosporine therapy should be adjusted for effectiveness during cyclosporine therapy.431,476,477 When adequate adjustment of antihypertensive therapy is not possible or is not tolerated, cyclosporine should be withdrawn.431,476,477

Measurements that should be obtained for baseline include serum creatinine concentration determined on 2 occasions, BUN, complete blood cell count, and serum concentrations of magnesium, potassium, uric acid, and lipoproteins.431,476,477 Serum creatinine must be monitored frequently.431,476,477 During the first 3 months of therapy with cyclosporine in the management of psoriasis, serum creatinine concentration and BUN should be evaluated every 2 weeks; thereafter, stable patients should be evaluated monthly.431,476,477 When the serum creatinine concentration exceeds baseline by 25% or more, repeated measurement should be obtained within 2 weeks.431,476,477 The dosage of cyclosporine should be reduced by 25-50% if the serum creatinine concentration on repeated measurement continues to exceed baseline by 25% or more.431,476,477 Such reduction of the dosage also is necessary if serum creatinine concentration exceeds baseline by 50% or more at any time .431,476,477 If the serum creatinine concentration does not decrease to within 25% of baseline after the dosage was modified twice, the drug should be withdrawn.476,477 Serum creatinine concentration also should be monitored after concomitant therapy with a NSAIA is modified by an increase in dosage and after initiation of new NSAIA therapy.431,476,477

Complete blood cell count and serum concentrations of magnesium, potassium, uric acid, and lipids should be monitored every 2 weeks during the first 3 months of therapy with cyclosporine in the management of psoriasis; thereafter, these values should be monitored monthly in stable patients or more frequently when the dosage is adjusted.431,476,477 Mild hypomagnesemia and hyperkalemia that are asymptomatic and increases in the serum concentration of uric acid may occur with cyclosporine.431,476,477 Serum concentrations of triglycerides or cholesterol may be increased modestly during therapy with cyclosporine.431,476,477 The dosage of cyclosporine should be reduced by 25-50% in response to any abnormality of clinical concern.431,476,477

Patients receiving cyclosporine to treat psoriasis should be warned about appropriate protection from the sun and avoidance of excessive solar exposure.431

Crohn's Disease

For the management of refractory, inflammatory or fistulizing Crohn's disease†, cyclosporine has been administered initially in a dosage of 4 mg/kg daily for about 2-10 days, as a continuous IV infusion over 24 hours. Most of those who responded were switched to oral cyclosporine (5-8 mg/kg daily) for a mean duration of about 2.5-12.2 (range: 0.5-37 months) months.

Cautions ⬆ ⬇

[Section Outline]

Renal Effects
Cardiovascular Effects
Nervous System Effects
Dermatologic Effects
Hepatic Effects
GI Effects
Infectious Complications
Hematologic Effects
Sensitivity Reactions
Other Adverse Effects
Precautions and Contraindications
Pediatric Precautions
Geriatric Precautions
Mutagenicity and Carcinogenicity
Pregnancy, Fertility, and Lactation

Patients who experienced adverse effects during treatment with cyclosporine for rheumatoid arthritis were affected principally by renal dysfunction, hypertension, headache, hirsutism/hypertrichosis, and GI disturbances.431 Therapy with cyclosporine was discontinued in clinical studies because of elevated serum creatinine concentration or hypertension in about 7 or 5% of patients, respectively, treated with the drug for rheumatoid arthritis at dosages within the recommended range.431 Reversibility of these changes generally occurred with timely reduction of the dosage or withdrawal of cyclosporine.431 Elevation of serum creatinine concentration increases in frequency and severity as the dosage of cyclosporine and its duration of administration increase.431 Maintenance of the regimen is likely to result in more pronounced increases in serum creatinine concentration.431

Patients who experienced adverse effects during treatment with cyclosporine for psoriasis were affected principally by renal dysfunction, hypertension, headache, paresthesia or hyperesthesia, hirsutism/hypertrichosis, abdominal discomfort, diarrhea, nausea/vomiting, influenza-like symptoms, hypertriglyceridemia, lethargy, and musculoskeletal or joint pain.431 Therapy with cyclosporine was discontinued in clinical studies because of elevated serum creatinine concentration or hypertension in about 5 or 1% of patients, respectively, treated with the drug for psoriasis at dosages within the range recommended.431,466 Elevation of blood pressure or serum creatinine concentration in patients receiving cyclosporine for the management of psoriasis generally was reversible after dosage reduction or withdrawal of the drug.431 Elevation of serum creatinine concentration increases in frequency and severity as the dosage of cyclosporine and its duration of therapy increase.431 Maintenance of the regimen is likely to result in more pronounced increases in serum creatinine concentration that may lead to irreversible renal damage.431 Progressive renal failure led to the death of a patient who developed renal deterioration while receiving cyclosporine for the treatment of psoriasis and continued to receive the drug.431

Renal Effects

The most frequent and clinically important adverse effect of cyclosporine is nephrotoxicity.1,2,129 Nephrotoxic effects (usually manifested as increased BUN and serum creatinine concentrations) of cyclosporine have been observed in 25-32, 38, or 37% of patients receiving the drug for kidney, heart, or liver allografts, respectively.1,2 Elevations of BUN and serum creatinine concentrations resulting from cyclosporine therapy appear to be dose related, may be associated with high trough concentrations of the drug, and are usually reversible upon discontinuance of the drug.1,3,9,76 Clinical manifestations of cyclosporine-induced nephrotoxicity may include fluid retention, dependent edema, and, in some cases, a hyperchloremic, hyperkalemic metabolic acidosis.132,140,141,142,143,164 The risk of cyclosporine-induced nephrotoxicity may be increased in patients receiving other potentially nephrotoxic agents.1 Mild cyclosporine-induced nephrotoxicity generally occurs within 2-3 months after transplantation.1 Although some decline from preoperative levels generally occurs in patients with mild nephrotoxicity, the BUN and serum creatinine concentrations reportedly become stabilized in the range of 35-45 mg/dL and 2-2.5 mg/dL, respectively, in these patients; however, these elevations often respond to dosage reduction.1 In some patients, more severe nephrotoxic effects have been observed early after transplantation and have been characterized by rapid increases in BUN and serum creatinine concentrations;1,66 these elevations usually respond to dosage reduction.1

Differentiation of Nephrotoxicity and Allograft Rejection

In patients with renal allografts, acute episodes of allograft rejection must be differentiated from nephrotoxic effects of cyclosporine.1,391 When increased serum creatinine concentrations occur without the usual symptoms of renal allograft rejection (e.g., fever, graft tenderness or enlargement), cyclosporine-induced nephrotoxicity is likely.1,76 Although reliable and sensitive differentiation of cyclosporine-induced nephrotoxicity from renal allograft rejection through specific diagnostic criteria currently is not possible,1,9,66,170,391 and nephrotoxicity and rejection may coexist in up to 20% of patients,170,333,391 either adversity has been associated with various parameters (e.g., history, clinical, laboratory, biopsy, aspiration cytology, urine cytology, manometry, ultrasonography, magnetic resonance imagery, radionuclide scan, and response to therapy) that can be used in an attempt to differentiate between the two.170,333,391 For example, nephrotoxicity from cyclosporine has been associated with a history of having undergone a transplant involving prolonged kidney preservation time170,288,303,333,391 or prolonged anastomosis time,170,288,333,391 having received concomitant therapy with nephrotoxic drugs (e.g., an aminoglycoside, a nonsteroidal anti-inflammatory agent),170,263,333,391 or having received an organ from a donor who was older than 50 years of age170,288,303,333,391 or who was hypotensive,170,333,391 whereas renal allograft rejection has been associated with a history of antidonor immune response or previous renal allotransplantation.170,288,333,391 Nephrotoxicity often becomes apparent clinically more than 6 weeks postoperatively in patients whose allograft functioned initially170,288,333,391 or as prolonged initial nonfunction of the allograft that resembles acute tubular necrosis,170,302,333,391 whereas renal allograft rejection often becomes apparent clinically less than 4 weeks postoperatively170,269,297,333,391 and manifests with signs such as fever exceeding 37.5°C,170,288,289,290,302,333,391 swelling and tenderness of the graft,170,288,290,333,391 weight gain exceeding 0.5 kg,170,289,290,291,333,391 and a decrease in daily urine volume by more than 500 mL or 50%.170,288,289,290,302,333,391

In some studies, patients with nephrotoxicity had high trough concentrations of cyclosporine in biologic fluid, as measured with a nonspecific (e.g., polyclonal radioimmunoassay [RIA] now obsolete) or a specific (e.g., high-performance liquid chromatography [HPLC]) assay for cyclosporine.275,276,282,278 The manufacturers state that a trough serum concentration of cyclosporine, as measured by polyclonal RIA, exceeding 200 ng/mL has been associated with the occurrence of nephrotoxicity.170,333,391,476,477 However, the relationship between nephrotoxicity and trough or other concentrations of cyclosporine in biologic fluid (e.g., whole blood) measured with specific monoclonal RIA or HPLC has not been fully established.279,280 By comparison, allograft rejection has been associated with low trough concentrations of cyclosporine in biologic fluid, as measured with a nonspecific (e.g., polyclonal RIA) or a specific (e.g., monoclonal RIA, HPLC) assay for cyclosporine.269,275,276,277,278,279,280,281,282,391 The manufacturers state that a trough serum concentration of cyclosporine, as measured by polyclonal RIA, of less than 150 ng/mL has been associated with the occurrence of rejection.170,333,391,476,477 Other concentrations of the drug in biologic fluid (e.g., whole blood) at which rejection occurred have been reported with the use of specific assays for cyclosporine.279,281

Common laboratory findings associated with cyclosporine-induced nephrotoxicity include a gradual increase in serum creatinine concentration (e.g., less than 0.15 mg/dL daily) that reaches a plateau of less than 25% above baseline,170,288,302,333,391 and a ratio of blood urea nitrogen (BUN) to serum creatinine of at least 20.170,288,302,333,391 By comparison, laboratory findings associated with allograft rejection include a rapid increase in serum creatinine concentration (e.g., exceeding 0.3 mg/dL daily) that reaches a plateau exceeding 25% above baseline,170,289,290,291,333,391 or a BUN to creatinine ratio of less than 20.170,333,391

The histologic features of allograft biopsies in patients with cyclosporine-induced nephrotoxicity include effects on the arterioles, tubules, and interstitium.9,170,269,333 Such findings include arteriolopathy manifested as medial hypertrophy and hyalinosis,170,269,297,333,391 nodular deposits, intimal thickening, endothelial vacuolization, and progressive scarring.170,333,391 Renal tubular effects of nephrotoxicity include atrophy,9,170,294,302,333,391 isometric vacuolization, and isolated calcifications.170,333,391 Interstitial effects of nephrotoxicity include minimal edema, mild focal infiltrates of mononuclear cells,170,269,294,297,333,391 and diffuse interstitial fibrosis that often is the striped form.9,170,333,391,392 The histologic features of allograft biopsies in patients with rejection include effects on the arterioles and arteries, tubules, interstitium, and glomeruli.170,269,295,297,333 Such findings include endovasculitis manifested as arteriolar and arterial endothelial cell proliferation,170,269,290,297,333,391 intimal arteritis,170,290,296,333,391 fibrinoid necrosis,170,294,333,391 and sclerosis.170,333,391 Renal tubular effects of rejection include tubulitis with erythrocyte and leukocyte casts170,269,290,294,297,333,391 and some irregular vacuolization.170,333,391 Interstitial effects of rejection include a diffuse moderate to severe infiltrate of mononuclear cells,170,269,290,294,297,333,391 edema,170,269,290,294,295,297,333,391 and hemorrhage.170,269,290,297,333,391 Glomerulitis, manifested as infiltration of glomerular capillaries by mononuclear cells, is associated with rejection.170,269,294,295,297,391 Histologic changes, including thromboses of arteriolar and glomerular capillaries and mesangial sclerosis, also have occurred in cyclosporine-treated patients with renal dysfunction following bone marrow transplantation.7

With cyclosporine-induced nephrotoxicity, renal allograft evaluation with aspiration cytology reveals deposits of the drug in tubular and endothelial cells and fine isometric vacuolization of tubular cells;170,261,267,333,391 urine cytology reveals tubular cells with vacuolization of cytoplasm and granularization.170,268,284,333,391 Manometry shows an intracapsular pressure of less than 40 mm Hg,170,293,299,333,391 and ultrasonography shows the renal cross-sectional area to be unchanged.170,264,333,391 With rejection, aspiration cytology shows that the graft generally is affected by an inflammatory infiltrate of mononuclear cells that includes phagocytes, macrophages, lymphoblastoid cells, and activated T-cells;170,261,283,298,301,333,391 HLA-DR antigens are expressed strongly by these mononuclear cells.170,283,333,391 Urine cytology in rejection may show degenerative renal tubular cells, plasma cells, and lymphocyturia exceeding 20% of the urinary sediment.170,288,333,391 Intrarenal manometry shows an intracapsular pressure exceeding 40 mm Hg in many patients with rejection,170,265,293,298,299,333,391 and ultrasonography shows an increase in graft cross-sectional area;170,264,333,391 the anteroposterior diameter is equal to or greater than the transverse diameter.170,333,391

In most patients with nephrotoxicity, magnetic resonance imagery shows normal renal appearance,170,266,286,333,391 and radionuclide scans performed with technetium Tc 99m pentetate (DTPA) and iodohippurate sodium I 131 to evaluate renal perfusion and tubular function, respectively, show renal perfusion to be normal (although a generally decreased perfusion is observed occasionally) and tubular function to be decreased.170,262,288,292,333,391 While the decrease in tubular function is a deteriorative effect, renal perfusion is not decreased to a deleterious extent.170,262,333,391 With rejection, findings of magnetic resonance imagery include loss of distinct corticomedullary junction,170,266,286,333,391 swelling of the allograft,170,286,333,391 image intensity of parenchyma that approaches the image intensity of psoas, and loss of hilar fat;170,333,391 radionuclide scans may show patchy arterial flow.170,288,333,391 Evaluation of renal perfusion and tubular function with technetium Tc 99m pentetate or iodohippurate sodium I 131, respectively, shows that renal perfusion is decreased to a greater extent than is tubular function in patients with rejection;170,292,391 uptake of indium In 111-labeled platelets170,285,287,333 or technetium Tc 99m in colloid is increased.170,300,333,391

Limited data suggest that some of the variables associated with nephrotoxicity actually may be risk factors for the development of nephrotoxicity from cyclosporine.263 The number of episodes of acute deterioration of renal function induced by cyclosporine (e.g., increase in serum creatinine concentration corrected by a decrease in the dose of cyclosporine), trough concentrations of cyclosporine during the second and third months after transplantation, the number of episodes of unexplained acute deterioration of renal function (e.g., increase in serum creatinine concentration unresponsive to a decrease in the dose of cyclosporine), and the number of treatments for rejection (e.g., corticosteroids) were correlated with chronic nephrotoxicity (e.g., arteriolopathy, striped form of interstitial fibrosis, tubular atrophy).263 The variables that were discriminative of nephrotoxicity included the number of episodes of acute deterioration of renal function induced by cyclosporine, the number of episodes of unexplained acute deterioration of renal function, the number of episodes of rejection, and the number of treatments for rejection,263 with patients with nephrotoxicity having experienced more episodes of acute deterioration of renal function, whether induced by the drug or unexplained, than patients with rejection, and those with rejection exhibiting a stronger history of multiple episodes of rejection and being treated for such more often.263 Some patients with chronic nephrotoxicity did not exhibit acute cyclosporine-induced deterioration of renal function.263 Poor primary function of the allograft occurred more often in these patients than in patients who had both acute deterioration of renal function induced by cyclosporine and chronic nephrotoxicity. 263

Response to a reduction in cyclosporine dosage generally can distinguish nephrotoxicity from rejection since the renal function of patients with nephrotoxicity usually recovers with such dosage modification.170,288,333,391 By comparison, response (e.g., in renal function) to an increase in dosage of concomitant corticosteroids or to antithymocyte globulin generally indicates the presence of rejection rather than nephrotoxicity.170,333,391

A form of cyclosporine-associated nephropathy that is characterized by serial deterioration in renal function and changes in renal morphology also has been described.391 In this nephropathy, the rise in serum creatinine concentration does not diminish in response to a decrease in the dosage of, or discontinuance of therapy with, cyclosporine in 5-15% of allograft recipients.170,391 Renal biopsy in such patients will show one or more morphologic changes, none of which is entirely specific to structural nephrotoxicity associated with cyclosporine, although diagnosis of such nephropathy requires evidence of these changes.391 The morphologic changes include renal tubular vacuolization, tubular microcalcifications, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy.336,377,391 Of interest in the consideration of the development of cyclosporine-associated nephropathy is that the appearance of interstitial fibrosis reportedly is associated with higher cumulative doses of cyclosporine or persistently high circulating trough concentrations of the drug, particularly during the first 6 months after transplantation when dosages tend to be highest.391 Furthermore, renal allografts appear to be most vulnerable to the toxic effects of cyclosporine during this time.170,391 Other factors that contribute to the development of interstitial fibrosis include prolonged perfusion time, warm ischemia time, and episodes of acute toxicity and acute or chronic rejection.170,391 Whether interstitial fibrosis is reversible and its correlation to renal function are not known.170,391 Arteriolopathy reportedly was reversible when the dosage of cyclosporine was decreased or therapy with the drug was discontinued.391

Management of Nephrotoxicity

Gradual reduction of cyclosporine dosage is recommended for the management of nephrotoxicity, with careful patient assessment for several days to weeks.2 When patients are unresponsive to reduction of cyclosporine dosage and the possibility of allograft rejection has been excluded, switching from cyclosporine to therapy with alternative immunosuppressants (e.g., azathioprine and prednisone) should be considered.2,9 Concomitant use of corticosteroids with cyclosporine does not appear to improve renal function.9

Other Renal Effects

Hyperkalemia2,11,88,129,132,143,167 (that may be associated with hyperchloremic metabolic acidosis),170,391 hypomagnesemia,132,136,144,145 and decreased serum bicarbonate concentration2,11 have been reported frequently in patients receiving cyclosporine; these effects may result from nephrotoxic effects of the drug.2,11,129,132,136 Hyperuricemia also occurs commonly in cyclosporine-treated patients,2,11,132,134,146,147,148,149,170,391 particularly in those receiving diuretics concurrently, and may result in gout in some patients.134,148 Although not clearly established, hyperuricemia appears to result at least in part from decreased renal clearance of uric acid.132,134,146,147,148 Hematuria has occurred rarely in patients receiving cyclosporine.1

Impairment of renal function (e.g., increased BUN and serum creatinine concentrations, decreased glomerular filtration rate (GFR) and effective renal plasma flow) and morphologic evidence of renal injury (e.g., renal tubular atrophy, interstitial fibrosis, arteriolar hyalinosis) have been observed in some patients who received short- or long-term treatment with cyclosporine for psoriasis.381,382,383,384,385,386,387,388,389,390 Elevated serum creatinine concentrations452,466 occurred in about 20% of patients.452 Elevations of BUN and serum creatinine concentrations resulting from cyclosporine at dosages used for psoriasis may be associated with relatively high trough concentrations of the drug but usually are reversible after discontinuance of the drug.383,385,388 Although limited data suggested the reversibility of decreases in GFR and effective renal plasma flow resulting from cyclosporine therapy for psoriasis, these manifestations of renal impairment may persist despite discontinuance of the drug.382,386 In patients who developed nephrotoxicity, as indicated by a decrease of more than 20% in GFR or a decrease of more than 25% in total renal blood flow, after 3 months of treatment with cyclosporine, evaluation at 3 months subsequent to discontinuance of the drug showed recovery of GFR but not of renal blood flow.382 GFR and effective renal plasma flow continued to be decreased below baseline 4 months after discontinuance of cyclosporine in patients who received the drug for a median of 12 months at a dosage of 5 mg/kg daily for 3 months that was then reduced by 0.35 mg/kg daily every month until the minimum effective dose was achieved.386 In some patients who received cyclosporine for an average of 30 months at a dosage of up to 5 mg/kg daily, GFR and renal plasma flow rate were below the lower 2.5 percentile of normal compared with the renal function of healthy individuals matched for age and gender 1 month after discontinuance of the drug.387 Biopsies occasionally showed kidneys with structural damage manifested as renal tubular atrophy, interstitial fibrosis, and hyaline arteriolopathy that were graded as moderate.387 Mild tubulointerstitial scarring and glomerulosclerosis were observed in the other patients but a relationship to cyclosporine was not certain.387 A correlation between severity of renal injury and severity of recurrent acute nephrotoxicity was found, which suggests recurrent severe acute nephrotoxicity (i.e., serum creatinine increased by more than 90% above baseline) to be a risk factor for chronic nephrotoxicity from cyclosporine.387 Histologic evidence of renal tubular atrophy, arteriolar hyalinosis, and increases above normal in interstitium and obsolescent glomeruli have been observed in patients who received cyclosporine at a mean dosage of 3 mg/kg daily for an average of 5 years.389

Cyclosporine administered to treat rheumatoid arthritis resulted in serum creatinine concentrations increasing by at least 30 or 50% in up to 43-48 or 18-24% of patients, respectively.431 Maintenance of the regimen is likely to result in more pronounced increases in serum creatinine concentration that may lead to irreversible renal damage.452 The maximal increase in serum creatinine concentration may be a predictor of nephropathy from cyclosporine.431,468 Features suggesting nephropathy were observed in the renal biopsies of some patients with rheumatoid arthritis treated with cyclosporine for an average of 19 months.431,467 The dosage was 4 mg/kg daily or less in one of the patients.452 Dosage reduction or withdrawal of cyclosporine resulted in improvement in serum creatinine concentrations in most of these patients.452,467 Morphologic features that are identified with nephropathy induced by cyclosporine generally were not observed in renal biopsies from patients who had mostly completed 6 months of therapy with the drug and who did not appear to have renal dysfunction.471 Renal biopsies obtained by the 20th month of therapy with cyclosporine for rheumatoid arthritis and after 30-46 months of treatment showed morphologic changes compared with baseline that were not considered to be specific to nephropathy induced by the drug.472 In a limited study, differences in renal biopsies were not observed between patients with rheumatoid arthritis treated with cyclosporine at dosages less than 5 mg/kg daily for an average of 26 months and controls derived from autopsies of patients with rheumatoid arthritis.469,470 In the patients treated with cyclosporine, creatinine clearance that was measured or calculated was decreased from baseline by 26 or 24%, respectively, after 24 months of therapy.469 Cyclosporine administered to treat rheumatoid arthritis resulted in elevated BUN in 1% to less than 3% of patients.431

Renal tubular atrophy and interstitial fibrosis was observed in 21% of patients with psoriasis who received cyclosporine dosages of 1.2-7.6 mg/kg daily for an average of 23 months.431 Such structural damage to the kidney was shown on repeated biopsy in some of the patients who were maintained on various dosages of cyclosporine for an additional period averaging 2 years, so that 30% of patients were affected overall.431 Most of these patients were receiving at least 5 mg/kg daily of cyclosporine, which exceeds the highest dosage recommended, had been taking the drug for more than 15 months, and/or had a clinically important increase in serum creatinine concentration for more than 1 month.431 Discontinuance of therapy with cyclosporine resulted in normalization of serum creatinine concentration in most patients.431 Quantitative digital morphometric analysis showed an increase in the percentage of fibrotic area in the tubular interstitium after 3.5 years of therapy with 3-6 mg/kg daily of cyclosporine compared with evaluation 1 year earlier.463 After 2 years of receiving cyclosporine generally at a dosage of 2.5-6 mg/kg daily, all patients had abnormal renal morphology, although the renal biopsy was normal at baseline in many of the patients.456 Evaluation of biopsies for focal interstitial fibrosis and arteriolar hyaline wall thickening showed increases compared with baseline.456 The percentage of sclerotic glomeruli was increased compared with baseline after 4 years of therapy with cyclosporine.456

Cardiovascular Effects

The manufacturers state that mild to moderate hypertension occurs in about 50% of renal transplant recipients who receive cyclosporine and in most cardiac transplant patients receiving the drug.1,476,477 In one study in renal allograft recipients, hypertension occurred in about 40% of cyclosporine-treated patients; 2 of these patients developed malignant hypertension with associated seizures.16 In some patients with cardiac allografts who developed hypertension while receiving cyclosporine, therapy with hypotensive agents has been required.1,129

Hypertension generally develops within a few weeks after beginning cyclosporine therapy129,132,150,151,152,156,157,159,160,167 and affects both the systolic and diastolic blood pressure.132,167 Although the mechanism has not been clearly established,129,132,150,151,152,153,156,157,158,159,160 there is some evidence that hypertension may result from the renal vasoconstrictive effects of the drug.132,150,151,152,157,158,159 The manufacturers state that hypertension associated with cyclosporine therapy may respond to dosage reduction and/or antihypertensive therapy.107,476,477 However, some evidence from clinical studies suggests that response to antihypertensive therapy may be variable132,150,151,152,156,160 and that elevations in diastolic blood pressure may be more resistant to treatment than elevations in systolic pressure.129,132,149,156

Myocardial infarction has occurred rarely in patients receiving the drug.1

Cyclosporine administered to treat rheumatoid arthritis resulted in hypertension372,375,376,452 in up to about 26% of patients.431 Systolic hypertension (i.e., measurement of systolic blood pressure that twice exceeded 140 mm Hg) and diastolic hypertension (i.e., measurement of diastolic blood pressure that twice exceeded 90 mm Hg) developed in 33 and 19% of patients, respectively.431 Arrhythmia occurred in up to about 5% of patients.431 Abnormal heart sounds, cardiac failure, myocardial infarction, and peripheral ischemia each occurred in 1% to less then 3% of patients.431

Cyclosporine administered to treat psoriasis resulted in the development of hypertension (i.e., systolic blood pressure of 160 mm Hg or greater and/or diastolic blood pressure of 90 mm Hg or greater) in about 28% of patients.431

Nervous System Effects

Adverse nervous system effects occur frequently in patients receiving cyclosporine.1,11,16,25 Tremor reportedly occurs in 12-21, 31, or 55% of patients with kidney, heart, or liver allografts, respectively, who receive cyclosporine.1 In one study in renal allograft recipients, however, tremor occurred in about 40% of cyclosporine-treated patients.11 Cyclosporine-induced tremor may be manifested as a fine hand tremor, usually is mild in severity, may improve despite continued therapy, and/or may be alleviated by a decrease in dosage of the drug.107,129,132,141,160,161,162,163

Seizures (particularly when cyclosporine was used in combination with high-dose corticosteroids),1,104,105,106,107,129,130,131,138,170,391 headache, paresthesia, hyperesthesia, flushing, and confusion have been reported occasionally in patients receiving cyclosporine.1,11,16,107,138 There is some evidence that cyclosporine-induced seizures and other neurotoxicity may be associated with high blood or plasma concentrations of the drug,138,153,161,162,163,164,165 concurrent high-dose corticosteroid therapy,1,129,130,131,153,154 hypertension,70,74,129,150,153,164,165 and/or hypomagnesemia.106,129,130,131,132,138,144,145,153,155 Encephalopathy, manifested by impaired consciousness, seizures, visual changes (e.g., blindness), loss of motor function, movement disorders, and psychiatric disturbances, has been described in patients receiving cyclosporine; in many cases, such manifestations were accompanied by white-matter changes (documented by imaging procedures and pathologic findings).476,477,478,479 Adverse neurologic effects in most cases are reversible upon discontinuance of the drug or in some patients following dosage reduction.476,477,478,479

Optic disc edema with possible visual impairment secondary to benign intracranial hypertension has been reported rarely in patients receiving cyclosporine; this complication occurred more frequently in transplant recipients than in patients receiving the drug for other indications.476,477,478,479

Psychiatric disorders including anxiety, flat affect, and depression have occurred rarely in patients receiving the drug.1,16,25,141,144,145

Cyclosporine administered to treat rheumatoid arthritis resulted in headache368,370,372,431 in up to about 25% of patients.431 Tremor368,370,371,373,374,375,376,431 or paresthesia367,368,370,375,431 occurred in up to about 13 or 11% of patients, respectively.431 Dizziness,431 depression,431 flushing,375,431 insomnia,431 or migraine occurred in up to about 8, 6, 5, 4, or 3% of patients, respectively.431 Hypoesthesia, neuropathy, and vertigo each occurred in 1% to less than 3% of patients.431 Psychiatric disorders that occurred in 1% to less than 3%431 of patients include anxiety,431 impaired concentration,431 confusion,431 emotional lability,431 decreased libido,431 increased libido,431 nervousness,376,431 paroniria,431 and somnolence.431

Cyclosporine administered to treat psoriasis resulted in adverse effects of the central and peripheral nervous system in about 26% of patients.431 Headache431,466 occurred in about 16% of patients.431 Paresthesia431,466 occurred in about 7% of patients.431 Dizziness,431 flushes,431 insomnia,431 nervousness,431 and vertigo431,466 each occurred in 1% to less than 3% of patients.431 Adverse psychiatric effects occurred in about 5% of patients.431

Dermatologic Effects

Adverse dermatologic effects including hirsutism and gingival hyperplasia have occurred frequently during cyclosporine therapy.1,11,16,25,129,132 The manufacturers state that hirsutism occurs in 21, 28, or 45% of patients with kidney, heart, or liver allografts, respectively, who received cyclosporine;1,476,477 however, hirsutism reportedly has been observed in 30-45% of renal allograft recipients in some studies.11,16,162,166 Hirsutism usually develops within 2-4 weeks after transplantation, is mild, and involves the face, arms, eyebrows, and back.129,141,166 Although most patients can tolerate cyclosporine-induced hirsutism,107,166 occasionally it can be severe16,160,166 and some patients may prefer cosmetic alleviation of the excess hair (e.g., by shaving or use of depilatories).107 In addition, although development of hirsutism does not appear to be dose related, improvement may occur following a decrease in dosage of the drug.107,162

Gingival hyperplasia reportedly occurs in 4-9, 5, or 16% of cyclosporine-treated patients with kidney, heart, or liver allografts, respectively,1 although in one study, gingival hyperplasia occurred in 30%11 of cyclosporine-treated patients. Cyclosporine-induced gingival hyperplasia is clinically similar to that observed with phenytoin therapy129,166 and appears to occur more frequently in pediatric patients.129,166 To reduce the risk of developing cyclosporine-induced gingival hyperplasia, careful oral hygiene should be maintained before and following transplantation.107,166 Gingival hyperplasia generally resolves 1-2 months following discontinuance of the drug;129,141,161,162 gingivectomy has been required rarely in patients with severe hyperplasia.16,129,166

Acne and brittle and abnormal fingernails occur occasionally in patients receiving cyclosporine.1,16,25,132,141

Cyclosporine administered to treat rheumatoid arthritis resulted in hypertrichosis367,368,370,371,372,373,375,376,431 or rash431 in up to about 19 or 12% of patients.431 Alopecia,431 gingival hyperplasia,367,370,372,373,374,431 or gingivitis431 each occurred in up to about 4% of patients.431 Bullous eruption or skin ulceration each occurred in up to about 1% of patients.431 Angioedema,431 dermatitis,372,431 dry skin,431 eczema,431 folliculitis,431 gingival bleeding,431 nail disorder,431 abnormal pigmentation,431 pruritus,431 skin disorder,431 and urticaria431 each occurred in 1% to less than 3% of patients.431

Cyclosporine administered to treat psoriasis resulted in adverse effects of the skin and appendages in about 18% of patients.431 Hypertrichosis431,466 occurred in about 7% of patients.431 Gingival hyperplasia431,466 occurred in about 4% of patients.431 Acne,431 dry skin,431 folliculitis,431,466 gingival bleeding,431 keratosis,431 pruritus,431 and rash431 each occurred in 1% to less than 3% of patients.431

Hepatic Effects

Hepatotoxicity has reportedly occurred in 4 or less, 7, or 4% of patients with kidney, heart, or liver allografts, respectively, usually during the first month of therapy with cyclosporine when higher dosages of the drug are used.1,16 Abnormalities of liver function test results (e.g., increased serum aminotransferase [transaminase] and gamma-glutamyl transferase concentrations) and increased serum bilirubin concentration are signs of cyclosporine hepatotoxicity.1,2,16,25 Reduction of cyclosporine dosage usually reverses the hepatotoxic effects of the drug;1,16 in one study, hepatotoxicity was associated with trough serum concentrations (determined by RIA) greater than 1000 ng/mL.16 Although increased serum alkaline phosphatase concentration has also been reported,11,16 it appears to be from bone rather than liver origin.11

Hyperbilirubinemia occurred in 1% to less than 3% of patients with psoriasis receiving cyclosporine.431 Hyperbilirubinemia that was minor and related to dosage has been observed without evidence of hepatocellular damage.431

GI Effects

Adverse GI effects, including diarrhea, nausea and vomiting, anorexia, and abdominal discomfort have occurred frequently during cyclosporine therapy.1,11,16,25 Gastritis, hiccups, and peptic ulcer have occurred less frequently.1 Constipation, difficulty in swallowing, and upper GI bleeding have been reported rarely in patients receiving the drug.1,16

Cyclosporine administered to treat rheumatoid arthritis resulted in nausea,367,368,371,374,375,431 abdominal pain,431 diarrhea,373,431 or dyspepsia367,368,373,431 in up to about 23, 15, 13, or 12% of patients, respectively.431 Vomiting, 374,431 flatulence,431 or GI disorder that was not otherwise specified431 occurred in up to about 9, 5, or 4% of patients, respectively.431 Anorexia or rectal hemorrhage each occurred in up to about 3% of patients.431 Stomatitis occurred in up to about 7% of patients.431 Constipation,431 dysphagia,431 eructation,431 esophagitis,431 gastritis,431 gastroenteritis,431 glossitis,431 salivary gland enlargement,431 tongue disorder,431 tooth disorder,431 gastric ulcer,367,431 and peptic ulcer431 each occurred in 1% to less than 3% of patients.431

Cyclosporine administered to treat psoriasis resulted in adverse GI effects in about 20% of patients.431 Nausea,431,466 diarrhea,431 abdominal pain,431 or dyspepsia431 occurred in about 6, 5, 3, or 2% of patients.431 Abdominal distention, increased appetite, and constipation each occurred in 1% to less than 3% of patients.431

Infectious Complications

Infectious complications, including pneumonia, septicemia, abscesses, and urinary tract, viral, local and systemic fungal, and skin and wound infections, have occurred frequently during cyclosporine therapy.1,11,16 When infectious complications occurring during cyclosporine therapy were compared with those occurring during combined azathioprine and corticosteroid therapy in one study, the frequency of bacterial, viral, and fungal infections was similar in both groups.11 However, in another study, septicemia, abscesses, and cytomegalovirus infections occurred less frequently in patients receiving cyclosporine than in those receiving azathioprine and corticosteroids; the frequency of other viral infections, local fungal infections, urinary tract infections, pneumonia, and wound and skin infections was similar in both groups.16

Cyclosporine administered to treat rheumatoid arthritis resulted in respiratory infection that was not otherwise specified, influenza-like symptoms, urinary tract infection, or pneumonia376,452 in up to about 9, 6, 3 or 1% of patients, respectively.431 Abscess,431 bacterial infection,431 cellulitis,431 fungal infection,431 herpes simplex,431 herpes zoster,376,431 moniliasis,431 renal abscess,431 and viral infection431 each occurred in 1% to less than 3% of patients.431

Cyclosporine administered to treat psoriasis resulted in infection or potential infection in about 25% of patients.431 Influenza-like symptoms or upper respiratory tract infections occurred in about 10 or 8% of patients, respectively.431 In addition, respiratory infection or viral and other infections of the respiratory system occurred in 1% to less than 3% of patients.431

Hematologic Effects

Adverse hematologic effects of cyclosporine reportedly occurring occasionally include leukopenia, anemia, and thrombocytopenia.1 Renal and other (e.g., bone marrow) allograft recipients who received cyclosporine as well as some patients who received the drug for other conditions (e.g., uveitis) have developed a syndrome of thrombocytopenia and microangiopathic hemolytic anemia.1,170,337,338,339,340,391 This vasculopathy is pathologically similar to the hemolytic uremic syndrome, with manifestations that include thrombosis of the 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 and such findings are generalizable to other immunosuppressive agents used after transplantation.170,391 Although graft failure can result from this syndrome, rejection is not conditional to such vasculopathy, which occurs with avid platelet consumption within the allograft, as shown by indium-111 labeled platelet studies.170,340,391 Neither the pathogenesis nor optimal management of the syndrome are clear.1,391 Although resolution has occurred after reduction of the dosage or discontinuance of cyclosporine, and therapy with streptokinase and heparin or with plasmapheresis, the efficacy of such interventions appears to depend on early detection with indium-111 labeled platelet scans.170,338,340,391 Lymphoma has also occurred occasionally.1,9 Evidence from animal studies and clinical studies in humans indicates that cyclosporine does not appear to depress bone marrow function.1 In one study, bone marrow depression occurred in 12% of patients receiving azathioprine and corticosteroids but did not occur in cyclosporine-treated patients.11 In another study, leukopenia (leukocyte count less than 2000/mm³) occurred in only one cyclosporine-treated patient while it occurred in about 10% of patients receiving azathioprine and corticosteroids.16

Cyclosporine administered to treat rheumatoid arthritis resulted in anemia, leukopenia, or lymphadenopathy in 1% to less than 3% of patients.431

Cyclosporine administered to treat psoriasis resulted in adverse effects related to leukocytes and the reticuloendothelial system in about 4% of patients.431 Platelet, bleeding, and clotting disorders or red blood cell disorder occurred in 1% to less than 3% of patients.431

Sensitivity Reactions

Sensitivity reactions1 (including anaphylaxis)1,49 have reportedly occurred in 2% or less of patients receiving cyclosporine.1 Anaphylaxis has been reported in 0.1% of patients receiving the drug IV.1 There have been no reports to date of anaphylaxis following administration of cyclosporine as conventional (nonmodified) liquid-filled capsules or oral solution (which do not contain polyoxyl 35 castor oil);1,170 in addition, some patients who developed anaphylaxis while receiving the drug IV subsequently received the conventional oral solution without unusual adverse effect.1 Anaphylactic reactions to IV cyclosporine include flushing of the face and upper thorax,1 acute respiratory distress with dyspnea1,49 and wheezing,1 hypotension,1,49,70 tachycardia,1 and, rarely, death.1 Although the exact mechanism of these reactions is not known, an association with polyoxyl 35 castor oil in the vehicle of the commercially available concentrate for injection has been suggested.1,49 Polyoxyl 35 castor oil has been shown to cause anaphylactoid reactions in animals, including stimulation of histamine release and a hypotensive effect;51,52 death has occurred in some animals.51 An immunologic mechanism (e.g., antibody production, complement activation) has been suggested in some studies and case reports;51,52,53,54,58 it has also been suggested that polyoxyl 35 castor oil may enhance the immunogenicity of other agents such as drugs.52,56,64 Anaphylactic reactions have been associated with administration of other drugs in a polyoxyl 35 castor oil-containing vehicle;53,54,56,59 other reactions (e.g., severe edema, abnormal liver function test results, hyperlipidemia, decreased plasma viscosity) have also been associated with IV use of polyoxyl 35 castor oil-containing preparations.56,57,60,61,62,63 Although IV cyclosporine-induced anaphylactic reactions may subside in some patients when IV infusion of the drug is stopped,1,49 death resulting from respiratory arrest and aspiration pneumonia has occurred in at least one patient.1

Allergic reactions occurred in 1% to less than 3% of patients who received cyclosporine to treat rheumatoid arthritis.431

Other Adverse Effects

Hyperlipidemia and abnormalities in electrophoresis may occur in patients receiving IV cyclosporine,1 since the vehicle in the commercially available cyclosporine concentrate for injection (polyoxyl 35 castor oil) has been associated with the development of these effects.1,60,62 Although hyperlipidemia and lipoprotein abnormalities are reversible following discontinuance of the drug, their occurrence during cyclosporine therapy usually does not require discontinuance of the drug.1

Benign fibroadenoma of the breast has been reported in a few renal allograft recipients receiving cyclosporine alone.55 Although a definite causal relationship to the drug has not been established, fibroadenoma resolved in one patient following dosage reduction of cyclosporine.55

Other adverse effects reportedly occurring in at least 3% of patients receiving cyclosporine include sinusitis and gynecomastia.1,11 Conjunctivitis,1 edema,1 fever,1 hearing loss,1 hyperglycemia1 (possibly induced by concomitant corticosteroid therapy),16 muscle pain,1 and tinnitus1 have occurred in 2% or less of patients receiving the drug.1 Chest pain,1 hair breaking,1 joint pain,1 aseptic necrosis,16 lethargy,1 mouth sores,1 night sweats,1 pancreatitis,1 visual disturbances,1 weakness,1 musculoskeletal abnormalities,16 and weight loss have been reported rarely in patients receiving cyclosporine.1

Cyclosporine administered to treat rheumatoid arthritis resulted in increases in nonprotein nitrogen (NPN) in up to about 19% of patients.431 Edema that was not otherwise specified,370,431 pain,431 or leg cramps/involuntary muscle contractions431 occurred in up to about 14, 13, or 12% of patients, respectively.431 Upper respiratory tract disorders occurred in up to 14% of patients, respectively.431 Fatigue,376,431 chest pain,431 or hypomagnesemia370,431 each occurred in up to about 6% of patients.431 Arthropathy, coughing, dyspnea, ear disorder that was not otherwise specified, or pharyngitis each occurred in up to about 5% of patients.431 Micturition frequency, purpura, sinusitis, or accidental trauma each occurred in up to 4% of patients.431 Bronchitis,431 fever,368,431 rhinitis,431 or rigors431 each occurred in up to about 3% of patients.431 Menstrual disorder376,431 or leukorrhea occurred in up to about 3 or 1% of female patients; breast fibroadenosis, breast pain, and uterine hemorrhage each occurred in 1% to less than 3% of patients.431 Dysuria occurred in up to about 1% of patients.431 Other adverse effects that occurred in 1% to less than 3%431 of patients include arthralgia,431 asthenia,431 bilirubinemia,431 bone fracture,431 bronchospasm,431 bursitis,431 cataract,431 abnormal chest sounds,431 conjunctivitis,431 deafness,431 diabetes mellitus,431 dry mouth,431 enanthema,431 epistaxis,431 ocular pain,431 goiter,431 hematuria,431 hot flushes,431 hyperkalemia,370,374,431 hyperuricemia,431 hypoglycemia,431 joint dislocation,431 malaise,431 micturition urgency,431 myalgia,431 nocturia,431 overdose,431 polyuria,431 procedure not otherwise specified,431 pyelonephritis,431 stiffness,431 increased sweating,431 synovial cyst,431 taste perversion,431 tendon disorder,431 tinnitus,376,431 tonsillitis,431 urinary incontinence,431 abnormal urine,431 vestibular disorder,431 abnormal vision,431 weight decrease,431 and weight increase.431

Cyclosporine administered to treat psoriasis resulted in adverse effects in the body as a whole in about 29% of patients.431 Pain occurred in about 4% of patients.431 Chest pain, fever, and hot flushes each occurred in 1% to less than 3% of patients.431 Adverse effects of the urinary system occurred in about 24% of patients.431 Micturition frequency occurred in 1 to less than 3% of patients.431 Adverse effects related to resistance mechanism occurred in about 19% of patients.431 Serum concentrations of triglycerides increased to more than 750 mg/dL in about 15% of patients and serum concentrations of cholesterol increased to more than 300 mg/dL in less than 3% of patients.431 Elevated serum concentrations of triglycerides or cholesterol generally are reversible after dosage reduction or discontinuance of cyclosporine.431,457 Adverse effects of the musculoskeletal system occurred in about 13% of patients.431 Arthralgia occurred in about 6% of patients.431 Adverse metabolic and nutritional effects occurred in about 9% of patients.431 Adverse reproductive effects occurred in about 9% of female patients.431 Adverse effects of the respiratory system (e.g., bronchospasm, coughing, dyspnea, rhinitis) occurred in about 5% of patients.431 Abnormal vision occurred in 1% to less than 3% of patients.431 Uric acid may increase in concentration and attacks of gout431,466 occurred rarely with cyclosporine.431

Precautions and Contraindications

Cyclosporine should be used for therapeutic applications other than transplantation only by clinicians experienced in such use of immunosuppressive therapy.431 The risks and benefits of cyclosporine in the management of psoriasis should be weighed carefully since the drug is a potent immunosuppressive agent with a number of potentially serious adverse effects.431 At dosages used in organ transplant recipients, cyclosporine should be used only under the supervision of a clinician experienced in immunosuppressive therapy and the management of organ transplant patients.1,170,391,452 Management of patients during initiation of, or any major change in, cyclosporine therapy should be performed in facilities equipped with adequate laboratory and supportive medical equipment and staffed with adequate medical personnel.1,70,170,391 Although patients who are stabilized on cyclosporine may receive the drug as outpatients, periodic laboratory monitoring is required.70 The clinician responsible for cyclosporine maintenance therapy should have complete information necessary for appropriate follow-up of the patient.1,170,391

Immunosuppression with cyclosporine may result in increased susceptibility to infection, including serious infections with fatal outcomes, and the possible development of lymphoma.1,170,391,476,477,478,595 The increased risk of developing lymphomas and other malignancies, especially of the skin, associated with cyclosporine or other immunosuppressive therapy appears to be related to the degree and duration of immunosuppression irrespective of the specific drugs.170,391 Because of the increased risk for skin cancer, patients should be advised to limit ultraviolet light exposure.476,477,478 The manufacturer cautions that, although cyclosporine should be administered with corticosteroids, conventional (nonmodified) oral formulations of the drug and the concentrate for injection should not be administered concomitantly with other immunosuppressive agents since increased susceptibility to infection and risk of lymphoma may result.1,170 However, the manufacturers of the modified oral formulations (Gengraf^®, Neoral^®) state that these modified formulations 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 infection.391,476,477 In addition, such potential danger for oversuppression of the immune system requires that the benefits versus risks of therapeutic regimens containing multiple immunosuppressive agents be weighed carefully.391

Comparative risk remains to be elucidated as to whether the risk of developing lymphomas is greater, in general, in patients with rheumatoid arthritis receiving cyclosporine than in rheumatoid arthritis patients who are untreated or being treated with cytotoxic agents.431 Before therapy with cyclosporine for rheumatoid arthritis is initiated, as well as during its course, patients should be evaluated thoroughly for the presence of malignancies.431 The risk for malignancies may be increased with concurrent use of cyclosporine and other immunosuppressive agents through induction of excessive immunosuppression.431

The risk of developing malignancies of the skin and lymphoproliferative disorders is increased in patients receiving cyclosporine to treat psoriasis, although the relative risk of such occurrence with cyclosporine or other immunosuppressive agents is comparable.431 In addition, previous therapy with PUVA and, to a lesser extent, with methotrexate or other immunosuppressive agents, coal tar, UVB light, or other radiation increases the risk of developing malignancies of the skin.431 Before therapy with cyclosporine is initiated, as well as during its course, patients should be evaluated thoroughly for the presence of malignancies with consideration that psoriatic plaques may obscure malignant lesions.431 A biopsy should be obtained from dermatologic lesions that do not typify psoriasis, before therapy with cyclosporine commences.431 Cyclosporine should be administered only after suspicious lesions resolve completely and only if other therapies are not an option.431 Because excessive immunosuppression is possible that would place the patient at risk for malignancies to develop, therapy with methotrexate or other immunosuppressive agents, PUVA, UVB, or other radiation should not be administered concurrently with cyclosporine in the management of psoriasis.431 In addition, therapy with coal tar should not be administered concurrently with cyclosporine.431

Immunosuppressed patients are at an increased risk for opportunistic infections, including reactivation of latent viral infections.584,585,586,587,588,591,592,594,595 These include BK virus-associated nephropathy (BKVN), which has been reported in patients receiving immunosuppressants, including cyclosporine, mycophenolate, sirolimus, and tacrolimus.584,585,586,587,588,589,590,591,592,594,595 Primary infection with polyoma BK virus typically occurs in childhood; following initial infection, the virus remains latent, but reactivation may occur in immunocompromised patients.585,586,587,588,589,590,592 BKVN has principally been observed in renal transplant patients (usually within the first year posttransplantation) and may result in serious outcomes, including deterioration of kidney function and renal allograft loss.584,585,586,587,588,589,590,591,592,594,595 Risk of BK virus reactivation appears to be related to the degree of overall immunosuppression rather than use of any specific immunosuppressive agent; patients receiving a maintenance immunosuppressive regimen of at least 3 drugs appear to be at highest risk.585,586,587,588,589,590,591,592 Patients should be monitored for possible signs of BKVN, including deterioration in renal function, during therapy with cyclosporine;584,585,586,588,594,595 screening assays for polyomavirus replication also have been recommended by some clinicians.586,587,590,591 Early intervention in patients who develop BKVN is critical; a reduction in immunosuppressive therapy should initially be considered in such patients.584,585,586,587,588,590,591,592,594,595 Although a variety of other treatment approaches have been used anecdotally in patients with BKVN, including antiviral therapy (e.g., cidofovir), leflunomide, IV immunoglobulins, and fluoroquinolone antibiotics, additional experience and well-controlled studies are necessary to more clearly establish the optimal treatment of such patients.585,586,587,591,592

Cyclosporine should not be administered as therapy for psoriasis in patients with abnormal renal function, hypertension that is uncontrolled, or malignancies because such conditions may increase the risk for nephrotoxicity and hypertension.431 The presence of these conditions also contraindicates therapy with cyclosporine to manage rheumatoid arthritis.431

Because of the risk of anaphylaxis, IV cyclosporine should be reserved for patients unable to tolerate oral formulations of the drug.1,170 Patients receiving IV cyclosporine should be under continuous observation for at least the first 30 minutes following initiation of the IV infusion and should be closely monitored 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 whenever cyclosporine is administered IV.1,170 If anaphylaxis occurs, IV infusion of cyclosporine should be discontinued immediately and the patient given appropriate therapy (e.g., epinephrine, oxygen) as indicated.1,170

Any cyclosporine preparation is contraindicated in patients with known hypersensitivity to the drug, and the concentrate for injection or modified oral formulations also are contraindicated in those with known hypersensitivity to any ingredient in the formulation (e.g., polyoxyl 35 castor oil [Cremophor^® EL] or polyoxyl 40 hydrogenated castor oil [Cremophor^® RH40]).1,170,391,476,477

Blood or plasma concentrations of the drug should be monitored periodically in patients receiving conventional (nonmodified) oral formulations of cyclosporine (liquid-filled capsules or oral solution), since absorption of orally administered cyclosporine is reportedly erratic during long-term therapy.1,170,171,424 Because of the highly variable GI absorption of cyclosporine and the accumulation of data relating trough concentrations with efficacy, predose (trough) concentrations should be monitored.424 However, monitoring of blood or plasma concentrations of cyclosporine is not a substitute for renal function monitoring or tissue biopsies.391 When necessary (e.g., because of changes in oral absorption of the drug), dosage adjustment should be made 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 Monitoring of blood or plasma cyclosporine concentrations 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 of the posttransplantation period because of surgical techniques (e.g., bile duct management) or surgically induced liver dysfunction.12 In addition, patients with GI malabsorption syndromes may have difficulty in achieving therapeutic blood or plasma concentrations when the drug is administered orally.1,170 Blood or plasma concentrations of cyclosporine also should be monitored routinely in allograft recipients receiving modified oral formulations and periodically in patients with rheumatoid arthritis being treated with these preparations of cyclosporine so that toxicity secondary to high concentrations of the drug is avoided.431,476,477

Patients receiving cyclosporine should be informed of the necessity of routine laboratory testing (e.g., BUN and serum creatinine, bilirubin, and liver enzyme concentrations) for the assessment of renal and hepatic function.1,170,391 Patients should also be given careful dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia during cyclosporine therapy.1,170,391 In addition, they should be advised that oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and in relation to meals,170,391,424,476,477 and that any change in oral formulation of the drug requires the supervision of a clinician and should be done cautiously.170,391,476,477

At high dosages, cyclosporine may cause nephrotoxicity and/or hepatotoxicity.1,170,391 Renal allograft recipients who develop increased BUN and serum creatinine concentrations should be carefully evaluated before adjustment of cyclosporine dosage is initiated, since these increases do not necessarily indicate that organ rejection has occurred.1,170,391 The development of renal dysfunction at any time during the course of cyclosporine therapy requires close monitoring of the patient and frequent dosage adjustment may be required.1,170,391 In patients with persistently high elevations of BUN and serum creatinine concentrations who are unresponsive to adjustment of cyclosporine dosage, switching to other immunosuppressive therapy should be considered.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 cyclosporine dosage to an excessive level in an attempt to reverse the rejection episode.1,170,391

During therapy with cyclosporine in the management of psoriasis, renal function must be monitored since renal dysfunction and structural damage to the kidney are potential adverse effects.431 Nephrotoxicity may occur at recommended dosages, with increasing risk as the dosage and duration of therapy with the drug increases.431 The serum creatinine concentration and BUN may increase in patients receiving cyclosporine, reflecting a decrease in the glomerular filtration rate.431 The maximal increase in serum creatinine concentration may be a predictive factor for cyclosporine-induced nephropathy.431,468 Structural damage to the kidney and persistent renal dysfunction may result from cyclosporine when patients are monitored inadequately and adjustment of the dosage is improper.431 Geriatric patients should be monitored with particular care because renal function also decreases with age.431 Monitoring the serum creatinine concentration regularly and reducing the dosage when values exceed baseline by 25% or more help to lower the risk of nephropathy from cyclosporine.431 Elevated serum creatinine concentrations generally reverse upon timely cyclosporine dosage reduction or disontinuance.431 The risk of nephropathy from cyclosporine in patients with psoriasis also is decreased by initiating therapy with the drug at 2.5 mg/kg daily and not exceeding a maximum dosage of 4 mg/kg daily.431

Pediatric Precautions

Although there are no adequate and controlled studies to date in children, cyclosporine has been used in children as young as 6 months of age without unusual adverse effects;1,170 the modified oral formulations have been used in children as young as 1 year of age.391,476,477 Cyclosporine has been used in hepatic and renal allograft recipients 7.5 months to 18 years of age.40,41,50,133 Children receiving cyclosporine and low-dose corticosteroid therapy have shown increased patient and graft survival rates and fewer adverse systemic effects on growth and development than those receiving therapy with other immunosuppressive agents;40,41,50 however, some clinicians have reported an increased frequency of seizures, possibly related to concomitant hypertension or high-dose corticosteroid therapy, in children receiving cyclosporine.1,70,74,129,130,131,154,164,165,166 The possibility that serious nephrotoxicity, hypertension, and/or seizures may occur in children receiving the drug should be considered.41,74

The safety and efficacy of cyclosporine for the management of juvenile rheumatoid arthritis or psoriasis in children younger than 18 years of age have not been established.431,476,477

Geriatric Precautions

Although safety and efficacy of cyclosporine have not been specifically studied in geriatric patients, 17.5% of patients treated with the drug for rheumatoid arthritis in clinical studies were 65 years of age and older.431,476,477 Patients 65 years of age or older were more likely to develop systolic hypertension while receiving cyclosporine to treat rheumatoid arthritis in clinical studies.431,476,477 This age group also was more likely to have elevated serum creatinine concentrations that were 50% or more above baseline after 3-4 months of receiving cyclosporine.431,476,477

Mutagenicity and Carcinogenicity

Various tests have not shown cyclosporine to be mutagenic.1,170,391 No evidence of cyclosporine-induced mutagenesis or genotoxicity was observed with the Ames microbial mutagen test, the V-79-HGPRT test, the micronucleus assay in mice and Chinese hamsters, chromosome-aberration tests in Chinese hamster bone marrow, the mouse dominant lethal assay, or the DNA-repair test in sperm from mice treated with the drug.170,391 However, in an in vitro study that used human lymphocytes, high concentrations of cyclosporine appeared to induce sister chromatid exchange.170,391

In a long-term study, the frequency of lymphocytic lymphomas was increased in female mice and that of hepatocellular adenomas was increased in male mice receiving 4 mg/kg daily.1 Following long-term administration in rats, the frequency of pancreatic islet cell adenomas was higher than the control rate in rats receiving 0.5 mg/kg of cyclosporine daily.1,170,391 In these studies, cyclosporine was administered in doses 0.01-0.16 times the maintenance dose for humans.391 The development of hepatocellular carcinomas and pancreatic islet cell adenomas in mice and rats did not appear to be dose related.1,170,391

An increase in the incidence of malignancy is a recognized complication of immunosuppression in allograft recipients and patients with psoriasis or rheumatoid arthritis.170,391,431 Skin cancers and non-Hodgkin's lymphoma develop most commonly.170,391 Lesions may regress after reduction or discontinuance of immunosuppression.170,391 Patients treated with cyclosporine are at greater risk for the development of malignancies than is the normal, healthy population, although such risk is similar to patients treated with other immunosuppressive therapies.170,391

Lymphomas have developed in patients receiving cyclosporine alone or in combination with other immunosuppressive agents,1,9,16,29,43,86,170,391 and some patients have developed a lymphoproliferative disorder that resolved following discontinuance of the drug.1 The lymphomas and lymphoproliferative disorders appear to be associated with Epstein-Barr virus (EBV) infections.20,21,108 It has been suggested that cyclosporine may cause alteration of the antibody for EBV20 or may inhibit the cell-mediated response to EBV, resulting in the development of lymphoma.21 With the exception of corticosteroids, the manufacturer states that conventional (nonmodified) oral formulations of cyclosporine or the concentrate for injection should not be used concomitantly with other immunosuppressive agents, since the risk of lymphoma may be increased.1,9,29,170 However, the manufacturers of the modified oral formulations (Gengraf^®, Neoral^®) state that these modified formulations 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 infection.391,476,477 In addition, such potential danger for oversuppression of the immune system requires that the benefits versus risks of therapeutic regimens containing multiple immunosuppressive agents be weighed carefully.391

Although the risk of lymphoma appears to be greatest when there is substantial immunosuppression (i.e., concomitant use of multiple immunosuppressive agents),1,9,16,42 all immunosuppressed patients should be considered at risk for developing lymphoma.9 The nature and optimum management of posttransplant lymphomas and lymphoproliferative disorders in allograft recipients remain to be clearly established,43,108 and clinicians should consult specialized references for current methods of evaluation and management. Some clinicians suggest that immunosuppressive therapy with cyclosporine and corticosteroids should be reduced or discontinued in patients who develop posttransplant lymphomas or lymphoproliferative disorders.43 In one study, reduction of cyclosporine and/or prednisone dosage resulted in resolution of lymphomas but was not associated with allograft rejection.43 Squamous cell carcinoma occurred in one patient receiving cyclosporine following renal transplantation but has not been directly attributed to the drug.11

Lymphoma developed in several patients who received cyclosporine to treat rheumatoid arthritis.431 Epidemiologic analyses indicated a relationship between cyclosporine and lymphoma,431 but no relationship to other malignancies that have been reported, including skin cancers, diverse types of solid tumors, and multiple myeloma.431 Carcinoma or tumor not otherwise specified each occurred in 1% to less than 3% of patients who received cyclosporine.431

Patients receiving cyclosporine to treat psoriasis have developed malignancies, especially of the skin.431 Squamous cell carcinoma or basal cell carcinoma occurred in 0.9 or 0.4% of patients, respectively, who received the drug.431 In another aggregate of clinical studies, tumors were reported in about 2% of patients who received the drug.431 Malignancies of the skin that included squamous cell and basal cell carcinomas were reported in about 1% of patients who received cyclosporine.431 Most of these patients had been treated previously with PUVA and some had received prior therapy with methotrexate, coal tar, or UVB.431 A history of previous cancer of the skin or a lesion that was a potential predisposition to such cancer was present in some of the patients before therapy with cyclosporine began.431 The lymphoproliferative disorders that developed in patients receiving cyclosporine for psoriasis included in one patient each non-Hodgkin's lymphoma that required chemotherapy and mycosis fungoides that regressed spontaneously after withdrawal of cyclosporine.431 Benign lymphocytic infiltration occurred in some patients with spontaneous regression occurring after withdrawal of cyclosporine or, in one patient, while administration of the drug continued.431 Malignancies that involved various organs accounted for the rest of the patients affected to yield an incidence of about 1%.431 During postmarketing surveillance, several more patients were reported to have developed tumors while receiving cyclosporine for psoriasis.431 Cervical intraepithelial neoplasia developed in a patient with chronic plaque psoriasis treated for over 3 years with 3 mg/kg daily of cyclosporine.459

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and well-controlled studies using cyclosporine in pregnant women, the drug has been shown to be embryotoxic and fetotoxic in rats and rabbits when administered orally at maternally toxic doses.391 Fetal toxicity was observed in these animals at doses 0.8-5.4 times (corrected for body surface area) the human maintenance dose of 6 mg/kg.1,170,391 Cyclosporine caused increased prenatal and postnatal mortality and reduced fetal weight with related skeletal retardation in these rats and rabbits.1,391 In women who received cyclosporine therapy throughout pregnancy, premature birth (gestational age of 28-36 weeks) and reduced neonatal weight occurred consistently.170,391 Most of the pregnancies also were complicated by growth retardation (which may be severe), fetal loss, preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility, and fetoplacental dysfunction.137,170,391,431 Premature birth was the most frequent complication, while being small for gestational age and neonatal complications were less common.170,391 Malformations occurred in some neonates and in a few cases of fetal loss.170,391 A full-term neonate was born to a woman who underwent a renal transplant prior to conception and received 450 mg of cyclosporine alone daily throughout pregnancy,75 and other successful pregnancies have been reported in allograft recipients who received the drug daily during pregnancy.137,139,170 Abnormalities in renal function or blood pressure were not observed in a limited number of children 7 years of age or younger exposed to cyclosporine in utero.476,477,478,479

Cyclosporine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1,170,391 In patients with psoriasis, the risks and benefits of therapy with cyclosporine during pregnancy should be evaluated carefully, with discontinuance of therapy considered seriously because of possible disruption of the interaction between the mother and fetus.452

Fertility

Reproduction studies in rats receiving cyclosporine have not revealed evidence of impaired fertility.1,170,391

Lactation

Since cyclosporine is distributed into milk, nursing should be avoided in women receiving the drug.1,75,170,391,424

Drug Interactions ⬆ ⬇

[Section Outline]

Nephrotoxic Drugs
Immunosuppressive and Antineoplastic Agents
Potassium-sparing Drugs
Drugs and Foods Affecting Hepatic Microsomal Enzymes
St. John's Wort (Hypericum perforatum)
Vaccines
Other Drugs

Nephrotoxic Drugs

Interactions that may potentiate renal dysfunction are well substantiated between cyclosporine and various drugs, including aminoglycosides, vancomycin, co-trimoxazole, ciprofloxacin, melphalan, amphotericin B, ketoconazole, certain nonsteroidal anti-inflammatory agents (NSAIAs) (e.g., azapropazon [not commercially available in the US], diclofenac, naproxen, sulindac), cimetidine, ranitidine, fibric acid derivatives (e.g., fenofibrate, bezafibrate), methotrexate, colchicine, and tacrolimus; in some cases, the resultant potentiation of renal dysfunction resulted from the nephrotoxic potential of the interacting drug while in others it resulted from accumulation of cyclosporine induced by the interacting drug.170,335,391,476,477,478,479 If concomitant use of cyclosporine with such drugs is unavoidable, renal function should be monitored carefully.170,391

Since nephrotoxic effects may be additive, concomitant use of cyclosporine with potentially nephrotoxic drugs (e.g., acyclovir, aminoglycoside antibiotics, amphotericin B) should be avoided.1,76

Concomitant administration of cyclosporine and amphotericin B has produced additive nephrotoxicity.15 In bone marrow allograft recipients receiving cyclosporine alone, cyclosporine and amphotericin B, or amphotericin B and methotrexate, increases in serum creatinine concentration were substantially greater in patients receiving cyclosporine and amphotericin B compared with those receiving cyclosporine alone or amphotericin B and methotrexate.15 Since it may be dangerous (i.e., risk of allograft rejection) to completely discontinue cyclosporine therapy when serum creatinine increases in allograft recipients, it has been suggested that if concomitant amphotericin B therapy is necessary in these patients, cyclosporine be temporarily withheld until the trough serum cyclosporine concentration (determined by RIA) is less than 150 ng/mL and that subsequent dosage be adjusted accordingly;15 this reduction in cyclosporine dosage may decrease the risk of nephrotoxicity while maintaining adequate immunosuppression.15

Concomitant administration of cyclosporine and gentamicin has resulted in an increased risk of acute tubular necrosis in renal allograft recipients when compared with concomitant administration of ampicillin and cyclosporine or gentamicin alone.308,312 Therefore, administration of aminoglycosides should be avoided in renal allograft recipients who are receiving cyclosporine.308

Concomitant administration of cyclosporine and co-trimoxazole has resulted in increases in serum creatinine concentrations.303,312,378 Concomitant administration of cyclosporine and melphalan has resulted in renal failure, and plasma creatinine concentrations and BUN were within normal limits or did not deteriorate in patients treated with melphalan without subsequent administration of cyclosporine.303,308,313

In patients with rheumatoid arthritis, the combination of cyclosporine and naproxen or sulindac resulted in additive decreases in renal function, as determined with technetium Tc 99m pentatate (DTPA) and iodohippurate sodium I 131 or p -aminohippuric acid (PAH) clearances.431,460 However, calculated creatinine clearance did not distinguish NSAIAs from acetaminophen in patients receiving cyclosporine in a dosage stabilized to treat rheumatoid arthritis and 4 weeks of concomitant therapy with 200 mg daily of indomethacin, 200 mg daily of ketoprofen, 400 mg daily of sulindac, or 4 g daily of acetaminophen.465 Creatinine clearance differed between indomethacin and acetaminophen but the increase of 6% observed with acetaminophen compared with indomethacin was not considered clinical in magnitude.465

Concomitant administration of cyclosporine and diclofenac may increase the nephrotoxic potential of cyclosporine.168,169 In addition to increases in serum creatinine concentration,168,169,303,308,420,421,431 increased serum potassium concentrations and/or blood pressure have occurred in some patients receiving the drugs concomitantly.308,420,421 In patients with rheumatoid arthritis, concomitant administration of cyclosporine and diclofenac resulted in elevation of the AUC of diclofenac but did not affect blood concentrations of cyclosporine.431,461 Because blood concentrations of diclofenac have been observed to increase by approximately double with concomitant administration of cyclosporine and diclofenac, a lower dosage in the therapeutic range of diclofenac should be used in patients receiving this combination.431 Pharmacokinetic interactions of clinical importance have not been observed between cyclosporine and aspirin, indomethacin, ketoprofen, or piroxicam.431,462 However, because of the risk of additive decreases in renal function, patients with rheumatoid arthritis who are receiving concurrent therapy with cyclosporine and any NSAIA should be monitored with close attention to clinical status and serum creatinine concentration.391,431

Concomitant administration of cyclosporine and colchicine may increase concentrations of cyclosporine,170,177,179,180,181,182,183,186,391,429,430 resulting in additive nephrotoxic effects.476,477,478,479 Cyclosporine also may reduce clearance of colchicine increasing the potential for enhanced colchicine toxicity (myopathy, neuropathy), particularly in patients with renal impairment.476,477,478,479 Patients should be monitored closely for colchicine toxicity during concurrent administration with cyclosporine; colchicine should be discontinued or dosage of the drug reduced if toxicity occurs.476,477,478,479

Immunosuppressive and Antineoplastic Agents

With the exception of corticosteroids, the manufacturer states that conventional (nonmodified) oral formulations of cyclosporine or the concentrate for injection should not be used concomitantly with other immunosuppressive agents since the risk of lymphoma1,9,16,170 and susceptibility to infection1 may be increased. However, the manufacturers of the modified oral formulations (Gengraf^®, Neoral^®) state that these modified formulations 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 infection.391,476,477 In addition, such potential danger for oversuppression of the immune system requires that the benefits versus risks of therapeutic regimens containing multiple immunosuppressive agents be weighed carefully.391 The manufacturers state that patients with psoriasis should not receive cyclosporine concomitantly with other immunosuppressive agents since excessive immunosuppression may result.431,476,477

Concomitant administration of cyclosporine and sirolimus substantially increases blood sirolimus concentrations.476,477,478,479 Sirolimus should be given 4 hours following cyclosporine administration to minimize the effect on sirolimus concentrations.476,477,478,479 Elevated serum creatinine concentrations also have been reported in patients receiving sirolimus and full dosages of cyclosporine concurrently; such increases generally are reversible following cyclosporine dosage reduction.476,477,478,479

Concomitant administration of cyclosporine and methotrexate resulted in elevation of the AUC of methotrexate in patients with rheumatoid arthritis.431 In a limited study, the AUC of methotrexate increased by approximately 30% and the AUC of the metabolite, 7-hydroxymethotrexate, decreased by approximately 80% during coadministration of cyclosporine and methotrexate to patients with rheumatoid arthritis.431 However, the clinical importance of these observations is not known.431 Blood concentrations of cyclosporine did not appear to be affected by coadministration of cyclosporine and methotrexate.431

Potassium-sparing Drugs

Because cyclosporine may cause hyperkalemia, the manufacturers state that the drug should not be used concomitantly with potassium-sparing diuretics.1,170,391,476,477 Caution is advised and control of potassium concentrations recommended when cyclosporine is administered concomitantly with potassium-sparing drugs (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists) or potassium-containing drugs or in patients receiving a potassium-rich diet.476,477,478,479

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Because cyclosporine is extensively metabolized, the concentration of drug in biologic fluid (e.g., plasma, blood) may be altered by drugs or foods (e.g., grapefruit juice) that affect hepatic microsomal enzymes, especially cytochrome P-450 isoenzyme subfamily CYP3A.170,177,179,180,181,182,183,391,424,425,429,430 Drugs and foods that inhibit hepatic microsomal enzymes could decrease the metabolism of cyclosporine and increase its concentration in biologic fluid.170,177,179,180,181,182,183,186,391,429,430 This potential interaction has been well substantiated to occur between cyclosporine and diltiazem, nicardipine, verapamil, mibefradil, fluconazole, itraconazole, ketoconazole, voriconazole, clarithromycin, erythromycin, quinupristin/dalfopristin, methylprednisolone, allopurinol, amiodarone, bromocriptine, colchicine, imatinib, danazol, oral contraceptives, or metoclopramide.170,335,391,429,430,476,477,478,595 Drugs that induce cytochrome P-450 activity could increase the metabolism of cyclosporine and decrease its concentration in biologic fluid.170,391 This potential interaction has been well substantiated to occur between cyclosporine and nafcillin,303,308,391 rifampin,113,114,115,116,170,335,391 carbamazepine,170,303,308,335,391 oxcarbazepine,476,477,478,595 phenobarbital,107,170,335,391 phenytoin,107,117,118,119,170,335,391 octreotide,391 sulfinpyrazone, terbinafine, or ticlopidine.303,308,335,391,476,477,478,479 In addition, clinicians should be cautious about concurrent administration of cyclosporine with rifabutin.391 Although the effect of rifabutin on the metabolism of cyclosporine has not been studied, the metabolism of other drugs by the cytochrome P-450 system has increased with rifabutin. 391 Concomitant administration of cyclosporine with drugs that affect its metabolism requires monitoring of the concentration of cyclosporine in biologic fluid with appropriate adjustment of cyclosporine dosage.170,391

Azole-derivative Antifungal Agents

Concomitant administration of cyclosporine and ketoconazole has been reported to increase plasma concentrations of cyclosporine1,13,14,109 and serum creatinine concentrations.13,14,109 It has been suggested that ketoconazole may interfere with the metabolism of cyclosporine via hepatic microsomal enzyme inhibition,13,109,111 although other mechanisms may also be involved.110,111 When ketoconazole therapy is initiated in patients receiving cyclosporine, renal function and blood or plasma cyclosporine concentrations should be monitored; some clinicians also recommend that reduction in cyclosporine dosage or replacement of cyclosporine with another immunosuppressive agent be considered.14 Patients stabilized on both drugs may require an increase in cyclosporine dosage when ketoconazole is discontinued.111

Concomitant administration of cyclosporine and fluconazole has been reported to increase whole blood concentrations of cyclosporine,303,308,315,379 and such increase may be associated with nephrotoxic effects.308,316,317,379 Serum creatinine concentration increased in at least one patient receiving cyclosporine following initiation of fluconazole therapy at a dosage of 200 mg every other day.308,316,317,379 However, such changes were not observed in several other patients receiving fluconazole 100 or 200 mg daily.303,308,317,318,379 Increases in trough cyclosporine concentrations and serum creatinine concentration also occurred when fluconazole dosage was increased from 100 to 300 mg daily.319 Evidence suggests that fluconazole interferes with the metabolism of cyclosporine via hepatic microsomal enzyme inhibition.308,320

Concomitant administration of cyclosporine and itraconazole has been reported to increase whole blood or serum concentrations of cyclosporine and serum creatinine concentrations.308,312,321,322,323,324,379 Evidence indicates that itraconazole competitively inhibits the hydroxylation of cyclosporine via hepatic microsomal enzyme inhibition.308,320

Concomitant administration of cyclosporine and voriconazole also may increase blood or plasma cyclosporine concentrations.476,477,478,595

Macrolides

Concomitant use of cyclosporine and erythromycin may result in substantial increases in blood or plasma concentrations of cyclosporine1,120,121,122,123,124,125 and subsequent signs of cyclosporine toxicity (e.g., nephrotoxicity).121,122,123 Studies in healthy adults indicate that erythromycin can substantially decrease plasma clearance of cyclosporine,124 presumably by inhibiting hepatic metabolism of the drug,1,120,121,122,123,125 although the exact mechanism remains to be clearly determined.120,121,122,123,124,125 Cyclosporine and erythromycin should be used concomitantly with caution, and patients should be monitored for evidence of cyclosporine toxicity.120,121,122,123,125 Renal function and blood or plasma concentrations of cyclosporine should be monitored when erythromycin therapy is administered or discontinued in patients receiving cyclosporine or vice versa, and cyclosporine dosage adjusted appropriately as necessary.1,120,121,122,123,125

Concomitant use of cyclosporine and clarithromycin has resulted in increases in the whole blood concentration of cyclosporine.308,400,402 Elevation in serum creatinine concentration was uncommon.400

Corticosteroids

Concomitant administration of prednisolone with cyclosporine may result in decreased plasma clearance of prednisolone,77,170,391 and plasma concentrations of cyclosporine may be increased during concomitant therapy with cyclosporine and methylprednisolone.1,78 In addition, seizures have reportedly occurred in adult and pediatric patients receiving cyclosporine and high-dose corticosteroid therapy concurrently with cyclosporine.1,129,130,131,153,154,170,335,391 The mechanism for this interaction may involve competitive inhibition of hepatic microsomal enzymes.77,78 The potential drug interaction between cyclosporine and prednisolone or methylprednisolone and the possibility of exacerbated toxicity, as well as the need for appropriate dosage adjustment, should be considered when these drugs are administered concomitantly.174,175,176

Calcium-Channel Blocking Agents

Mibefradil (no longer commercially available in the US) inhibits the metabolism of cyclosporine, with resultant increased blood concentrations of the immunosuppressive agent; the possible need for cyclosporine dosage adjustment should be considered during concomitant mibefradil therapy.429,430 In addition, when cyclosporine is used in combination with mibefradil and an HMG-CoA reductase inhibitor (e.g., lovastatin, simvastatin), increased blood concentrations of cyclosporine and the HMG-CoA reductase inhibitor also may occur which potentially could lead to HMG-CoA reductase inhibitor-induced rhabdomyolysis; therefore, concomitant use of the drugs should be avoided.429,430

Concomitant administration of cyclosporine and verapamil has resulted in increased whole blood concentrations of cyclosporine.303,308,325,326,327,328,329,380 It has been suggested that verapamil may interfere with metabolism of cyclosporine via hepatic microsomal enzyme inhibition.325,326,380 However, evaluation of the effect of verapamil on the pharmacokinetics of the major metabolites of cyclosporine indicated that the interaction between cyclosporine and verapamil was not secondary to interference with N -demethylation.329

Concomitant administration of cyclosporine and nicardipine has resulted in increased whole blood or plasma cyclosporine concentrations.303,308,330,331,332,378,380 Concomitant administration of cyclosporine and nifedipine resulted in more frequent occurrence of gingival hyperplasia compared with cyclosporine alone.170,335,391,401

Concomitant administration of cyclosporine and diltiazem has resulted in increased blood cyclosporine concentrations126,127 and consequent cyclosporine-induced nephrotoxicity.126 Although further study is needed, it has been suggested that diltiazem may interfere with metabolism of cyclosporine via hepatic microsomal enzyme inhibition.126,127

Other Drugs Affecting Hepatic Microsomal Enzymes

Concomitant administration of cyclosporine and rifampin,1,112,113,114,115,116 phenytoin,1,107,117,118,119 phenobarbital,1,107 or a combination of IV sulfamethazine and trimethoprim (co-trimoxazole)1,73,391 reportedly has resulted in decreased cyclosporine concentrations, probably by increasing hepatic metabolism of the drug.1 Monitoring of plasma or blood cyclosporine concentrations and appropriate dosage adjustment are necessary when any of these drugs is used concomitantly with cyclosporine.1

Concomitant administration of cyclosporine and cimetidine has resulted in increased serum creatinine concentrations, although some evidence suggests that renal function may not be adversely affected despite a decrease in creatinine clearance.308,378,380 An increase in whole blood concentrations of cyclosporine occurred with concomitant administration of cyclosporine, cimetidine, and metronidazole.308,314,380 Concomitant administration of cyclosporine and ranitidine also has resulted in an increase in serum creatinine concentrations.308,378,380 However, some evidence indicates that serum creatinine concentration, creatinine clearance, and inulin clearance are affected minimally by the combination of cyclosporine and ranitidine.308,380

Clearance of lovastatin reportedly was reduced with concomitant administration of cyclosporine,170,391 and such alterations could result in toxic effects of the antilipemic agent.170,303,304,305,307,335,391 Adverse effects observed during concomitant cyclosporine and lovastatin therapy have included myositis,170,335,391 myolysis, or rhabdomyolysis.303,304,305,307,335 Manifestations of such myopathy included myalgia and/or muscle weakness and increases in serum creatine kinase concentration.303,304,305,306,307 Acute renal failure has occurred concurrently with myopathy.303,304,305,306,307

Combined use of mibefradil (no longer commercially available in the US), cyclosporine, and an HMG-CoA reductase inhibitor (e.g., lovastatin, simvastatin) can result in a potentially serious interaction and therefore should be avoided.303,304,305,306,307

Concomitant use of cyclosporine and allopurinol has resulted in increases in the whole blood concentration of cyclosporine.403,404 Serum creatinine concentration may also be elevated.404 Concomitant administration of cyclosporine and danazol also has resulted in increased blood cyclosporine concentrations and serum creatinine concentrations.303,308,334,378,380

Concomitant administration of cyclosporine and carbamazepine has resulted in decreased concentrations of cyclosporine in biologic fluid (e.g., whole blood) that were subtherapeutic in adults.303,308,309,379 In children whose dosage of cyclosporine was stabilized, trough concentrations of cyclosporine in whole blood were lower compared with control in patients treated concurrently with carbamazepine.399

Grapefruit Juice

Concomitant oral administration of grapefruit juice with cyclosporine has been reported to increase bioavailability of the drug.432,435,438,442,444,445,446,447,453,455 The interaction does not appear to occur with sweet (“common”) orange juice,432,434,439,441,443,450,454,455 but some evidence indicates that it is likely with sour (Seville) orange juice.66,450

In several studies in healthy adults432,435,453,455 or renal transplant recipients433,434,435,438,455 receiving cyclosporine as conventional (nonmodified) oral capsules432,433,438,453 with 175-250 mL of oral grapefruit juice,432,435,438,453,455 oral bioavailability of the drug increased by about 20-200%. Although it has been suggested that separating oral administration of cyclosporine and the juice by at least 90 minutes may minimize the effect on bioavailability, peak serum cyclosporine concentrations still may be increased,433,435,455 and other evidence suggests that the effect of grapefruit juice on drug bioavailability may persist much longer (e.g., for at least 10 hours), possibly secondary to a prolonged effect of the interacting constituent(s) on enzymes in the gut wall.66,449,451 Therefore, additional study is needed to determine whether separation of cyclosporine and grapefruit juice administration during the day can adequately minimize the potential interaction.66

The interaction between grapefruit juice and cyclosporine bioavailability appears to result from inhibition, probably prehepatic,435,436,438,443,448,449,450,451,453,455 of the cytochrome P-450 enzyme system by some constituent(s) in the juice;432,433,434,435,436,437,438,439,440,441,442,443,448,449,450,451,453,454,455 grapefruit juice does not interfere appreciably with metabolism following IV drug administration.436,443,449,453 Both fresh and frozen grapefruit juice have been shown to inhibit first-pass metabolism of drugs metabolized by various cytochrome P-450 isoenzymes, including CYP1A2,434,437,440,449,454,455 CYP2A6,437,454,455 and the CYP3A subfamily (e.g., CYP3A4);432,433,434,435,436,438,439,440,441,442,443,448,449,450,451,454,455 these enzymes are present in the liver and/or extrahepatic tissues such as intestinal mucosa.432,433,434,435,436,438,440,449,451,453,454,455 Following oral administration of cyclosporine,432,433,434,435,453,455 certain benzodiazepines (e.g., midazolam, triazolam),436,443,454,455 and certain calcium-channel blocking agents (e.g., 1,4-dihydropyridine derivatives),434,439,441,451,455 such prehepatic inhibition of drug metabolism by grapefruit juice appears mainly to involve the CYP3A4 isoenzyme, principally within the small intestinal wall (e.g., in the jejunum), thus increasing systemic availability of these drugs. The magnitude of this interaction may be particularly notable for drugs such as cyclosporine that exhibit poor oral bioavailability when administered alone and in individuals in whom oral bioavailability is already relatively low.432,434,454

The constituent(s) of grapefruit juice principally responsible for this interaction has not been elucidated fully.66,432,434,435,436,437,438,439,440,441,442,443,446,448,449,450,453,454,455 In addition, the composition of grapefruit juice is variable depending on natural and commercial factors.452 Such factors influencing individual concentrations of various grapefruit constituents include fruit variety, environmental conditions (e.g., temperature, humidity, location), fruit maturity, and juicing procedures (e.g., extraction pressure, method and extent of debittering, final adjustments of the juice product such as addition of essential oils and pulp).452 Grapefruit juice contains high concentrations of bioflavonoids, which have been shown to inhibit cytochrome P-450 microsomal enzymes.432,434,437,439,440,441,442,443,445,448,449,450,451,453,454 Although naringin, a bioflavonoid that gives grapefruit its characteristic bitter taste, has been a principal suspect because of the relatively high concentrations present in the fruit,434,440,443,445,448,450,453,454,455 in vitro and in vivo evidence indicates that this bioflavonoid probably has little or no effect on the inhibition of cytochrome P-450 enzymes.66,434,443,448,449,450,453,455 Naringenin, the aglycone metabolite of naringin, is a more potent inhibitor of cytochrome enzymes,440,441,448,450,451,453,455 but recent evidence suggests that this constituent may only contribute to, not be principally responsible for, grapefruit juice-induced drug interactions.66,449,450 Complicating interpretation of these data, however, are methodologic limitations of human studies that currently cannot elucidate the extent to which these or other flavonoids may contribute to the metabolic interactions.452 Further complicating interpretation are potential problems with extrapolating results obtained with hepatic microsomes to extrahepatic cytochromes since the interaction probably is prehepatic (i.e., involving the small intestine).452 In addition, the effects of flavonoids on metabolic reactions can be complex and, in some cases, the same flavonoid or possibly a metabolite can inhibit one reaction and stimulate another or even the same reaction in a concentration-dependent manner.452 Alternatively, some evidence indicates that 6',7'-dihydroxybergamottin, a furanocoumarin (psoralen) compound present in grapefruit juice but not in sweet orange juice, may be the main constituent responsible for such drug interactions involving cytochrome P-450 enzymes.66,449

Cyclosporine concentrations ideally are maintained in a relatively narrow range to prevent transplant rejection and minimize toxicity.444,453 Because concomitant oral administration of cyclosporine and grapefruit juice can result in clinically important increases in systemic concentrations of the drug, such administration should be avoided.435,444,445 Although some clinicians have suggested that grapefruit juice may provide a nontoxic and inexpensive alternative to drugs that have been used to improve oral bioavailability of cyclosporine and thus reduce the required dose of this expensive drug,66,442,453 others have cautioned that the resultant effects would be unpredictable since the composition of this juice is not standardized.445,446,447 The effect of grapefruit juice on oral bioavailability of the drug from the more bioavailable modified oral formulations (i.e., Gengraf^®, Neoral^®) remains to be established,66,445,455 but the manufacturers recommend that concomitant use of these formulations and the juice also be avoided.444,476,477

St. John's Wort (Hypericum perforatum)

Concomitant use of cyclosporine and St. John's wort ( Hypericum perforatum ) has resulted in marked reduction in the blood concentrations of cyclosporine, leading to subtherapeutic levels, rejection of transplanted organs, and graft loss.476,477,478

Vaccines

The possibility that the immune response to vaccination may be diminished in patients receiving cyclosporine should be considered.170,391 In addition, because of the immunosuppressive effects of cyclosporine, the manufacturers recommend that live vaccines be avoided during therapy with the drug.170,335,391,476,477

Other Drugs

Concomitant administration of cyclosporine and metoclopramide has resulted in increased area under the blood concentration-time curve of cyclosporine.303,378,380 It has been suggested that absorption of cyclosporine increased through acceleration of gastric emptying of the drug stimulated by metoclopramide.308,378 Concomitant use of cyclosporine and orlistat should be avoided because of the potential for decreased cyclosporine absorption.476,477,478,479

Concomitant use of bosentan and cyclosporine has resulted in decreased plasma cyclosporine concentrations by approximately 50% and increased steady-state plasma bosentan concentrations by about 3- to 4-fold.476,477,478,593 The manufacturer of bosentan states that concomitant use of bosentan and cyclosporine is contraindicated.593

Concomitant administration of cyclosporine and digoxin has resulted in decreases in apparent volume of distribution and serum clearance of digoxin.170,303,308,310,391 Cardiac glycoside toxicity (e.g., bidirectional ventricular tachycardia, anorexia, nausea, vomiting, diarrhea) occurred and serum digoxin concentrations were increased within a few days after patients already receiving digoxin began receiving cyclosporine.170,303,308,310,378,391 The mechanism of this interaction may involve the decrease in glomerular filtration rate induced by cyclosporine, since in dogs concomitant administration of cyclosporine and digoxin resulted in acute decreases in the renal clearance of the glycoside, glomerular filtration, and renal perfusion.311

Other Information ⬆ ⬇

[Section Outline]

Pathogenesis
Manifestations
Treatment
Immunosuppressive Effects
Renal Effects
Other Effects
Absorption
Distribution
Elimination
Chemistry
Stability

Acute Toxicity

Pathogenesis

Limited information is available on the acute toxicity of cyclosporine.1,170,391,424 The oral LD₅₀ of cyclosporine is about 2.3, 1.5, or greater than 1 g/kg in mice, rats, and rabbits, respectively.1,170,391 The IV LD₅₀ is 148, 104, or 46 mg/kg in mice, rats, and rabbits, respectively.1

Manifestations

Overdosage of cyclosporine is likely to produce symptoms that are mainly extensions of common adverse reactions.66 Transient hepatotoxicity and nephrotoxicity may occur but should resolve following elimination or discontinuance of the drug.1

Treatment

In acute oral cyclosporine overdose, the stomach should be emptied by inducing emesis.1 Induction of emesis is probably useful up to 2 hours after ingestion.1,391 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents.70,79 Supportive and symptomatic treatment should be initiated.1,170,391 Hemodialysis and charcoal hemoperfusion reportedly are not useful for enhancing the elimination of cyclosporine following overdosage.1,170,391 When overdosage occurs in patients prescribed cyclosporine therapy, the drug may be withheld for a few days or alternate-day therapy may be initiated until the patient is stabilized.70

Pharmacology

Immunosuppressive Effects

Cyclosporine mainly exhibits immunosuppressive activity.1,2,3,4 In vivo studies in animals have shown that cyclosporine 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.1,2 Cyclosporine has also been shown to inhibit primary and secondary responses to T cell-dependent antigens (e.g., xenogeneic [heterologous]erythrocytes) in animals.3 The drug may also inhibit humoral immune responses to some extent.1,2 Increased survival of allogeneic (homologous) transplants involving skin, heart, kidney, liver, pancreas, bone marrow, small intestine, and lung has been shown in animals receiving the drug.1,170,391

The exact mechanism(s) of immunosuppressive action of cyclosporine has not been fully elucidated but appears to mainly involve inhibition of lymphocytic proliferation and function.1,2,4,6 It has been suggested that the immunosuppressive action of cyclosporine results from specific and reversible inhibition of immunocompetent T cells (T-lymphocytes) in the G₀ (resting) or G₁ (first “gap,” postmitotic, or presynthetic) phase of the cell cycle.1 Cyclosporine mainly inhibits T-helper (inducer) cells;1,3,4 some inhibition of T-suppressor cells may also be involved.1 The drug also inhibits T-cytotoxic cells and interleukin-2-producing T cells.3 Cyclosporine inhibits production and/or release of lymphokines including interleukin-2 (T-cell growth factor)1,2 and interleukin-1 (lymphocyte-activating factor).2 Cyclosporine inhibits the release of interleukin-2 from activated T cells and also inhibits interleukin-2-induced activation of resting T cells; the drug does not appear to inhibit activation of resting T cells that is induced by exogenous interleukin-2.2

There is conflicting evidence to date whether cyclosporine affects B cells (B-lymphocytes).2 In some studies, cyclosporine inhibited B-cell responses to macrophage-processed antigens and directly suppressed B cells in the blastogenic phase.2 In other studies, cyclosporine did not inhibit B-cell antibody production.2 In animals, cyclosporine does not affect the function of phagocytic cells (enzyme secretion, chemotactic migration of granulocytes, macrophage migration, in vivo carbon clearance) or that of tumor cells (growth rate, metastasis).1

Unlike other currently available immunosuppressive agents (e.g., azathioprine), cyclosporine lacks clinically important myelosuppressive activity.1,2,6 In one study following administration of high dosages of cyclosporine, bone marrow cell counts (i.e., granulocytes, monocytes, stem cells) showed only slight reductions in cell numbers; proliferation of bone marrow stem cells was normal or enhanced.6

Renal Effects

Cyclosporine produces nephrotoxic effects which generally appear to be dose dependent and reversible.1,4 Increased BUN and/or serum creatinine concentrations have been observed during therapy with the drug.1,2 In some patients following bone marrow or renal transplantation, histologic evidence of nephrotoxicity has been observed including arteriolar and glomerular thrombi, marked tubular injury, and interstitial fibrosis.7,9 Ischemically injured kidneys may be particularly sensitive to the nephrotoxic effects of the drug.9,16 Hypertension, hyperkalemia, and hyperuricemia frequently result from therapy with cyclosporine and may be caused directly by the drug's nephrotoxic effects.2,11,88,107,129,132,134 Increased plasma renin activity has been reported in animals receiving cyclosporine and may contribute to the development of hypertension.2,30

Other Effects

There is some evidence that cyclosporine may have antimalarial,32,44 antineoplastic,33 and antischistosomal34 activity; however, the clinical importance of these findings has not been determined.70

Pharmacokinetics

Cyclosporine as unchanged drug is chiefly responsible for immunosuppressive activity,391,424 although certain metabolites (e.g., AM1, AM9, AM4N) appear to contribute, at least in part, to this activity.424,425 Determination of the pharmacokinetics of cyclosporine appears to be biologic fluid dependent (blood vs plasma or serum) and assay-method dependent (radioimmunoassay vs high-pressure liquid chromatography).10,47,67,76,84,87,425 Because of these apparent differences, interpretation of pharmacokinetic data and determination of a relationship between biologic fluid concentrations and therapeutic and/or toxic effects of the drug are difficult.10,47,84,87,425 Although the most appropriate biologic fluid and assay method for determining cyclosporine concentrations have not been fully established,83,84,425 most experts currently recommend that whole blood preferably be used391,424 since the higher cyclosporine concentrations present in this fluid (relative to plasma or serum) can be measured more precisely and accurately than with these other fluids.424 In addition, there is some evidence from renal allograft recipients that whole blood rather than plasma determinations may be a more useful guide to efficacy and/or toxicity of cyclosporine,277,279,424 although precise relationships remain to be established.170,391 In addition, these experts currently recommend that an assay method with high specificity for unchanged cyclosporine preferably be used.424 Some laboratories may continue to report, and clinicians to use, cyclosporine concentrations determined in plasma or serum,424 and, while the benefits remain unclear,424,425 some centers advocate the use of both nonspecific and specific assays in order to gain insight into the proportion of immunoreactivity resulting from metabolites of the drug.424 In addition, interpretation of results can be difficult, in part because of the complex pharmacokinetics of the drug, variety of assay methods used, and the broad range of acceptable values, depending on the clinical indication for cyclosporine use and time since transplantation.424,425 Therefore, all values for cyclosporine concentration must be qualified by the biologic fluid and assay method used,83,424 and any guidance regarding possible dosage adjustment should include information on appropriate reference ranges and be tailored to the patient population being treated and any associated treatment protocols.424

Distribution of cyclosporine into erythrocytes is temperature80,424,425 and concentration dependent;1,80,424 therefore, reported plasma concentrations are affected by temperature during the separation of plasma and may also be affected by concentration of the drug.80,83 Variability of plasma cyclosporine concentrations may be minimized by allowing the sample to equilibrate at room temperature for at least 1 hour prior to centrifugation.83 Determinations of drug concentration using anticoagulated, hemolyzed whole blood may avoid the problem of temperature-dependent redistribution of the drug between plasma and erythrocytes.83 Plasma concentrations of the drug may also be affected by the patient's lipoprotein concentration and hematocrit.10,80,82,425 Following administration of the same dose, blood concentrations of cyclosporine are higher than plasma concentrations since the drug is distributed into erythrocytes.1,70,76,424,425 Plasma and serum cyclosporine concentrations are comparable.66,67,83,424

Although both RIA and HPLC have been used to determine biologic fluid cyclosporine concentrations, RIA has been used most extensively since HPLC determination of cyclosporine concentrations is technically difficult and variable;10,46,83,424 the 2 assays do not yield comparable results.10,47,83,87,424 Both specific (for unchanged drug) and nonspecific RIA methods are available.424 When RIA methods that employ nonspecific monoclonal or polyclonal antibodies are used for monitoring cyclosporine concentrations, cross-reactivity of the antisera with circulating metabolites of cyclosporine has resulted in higher cyclosporine concentrations than when HPLC is used.46,47,83,424 The ratio of specific (either RIA or HPLC) to nonspecific assays of blood cyclosporine concentrations has varied from 1:1 to 1:8;10,424 however, for nonspecific immunoassays, the ratio usually is 1:2 to 1:3 for stable renal allograft patients several months after surgery but is 1:3 to 1:4 for cardiac or hepatic allograft recipients, and may be as great as 1:19 in hepatic allograft recipients with severe cholestasis.424 The ratio may remain constant for fixed points of comparison during the dosing interval.83 Additional study is needed to determine whether a similar constancy for these fixed-point ratios exists in patients with impaired hepatic function, especially during the early posttransplantation period in hepatic allograft recipients, since cyclosporine is metabolized principally in the liver and undergoes substantial biliary elimination.83 In addition to RIA, immunoassay methods currently employed include a nonspecific or specific fluorescence polarization immunoassay (FPIA) and a specific enzyme multiplied immunoassay technique (EMIT).424 Even with specific immunoassays, some cross-reactivity with cyclosporine metabolites may exist, resulting in slightly different reference ranges for cyclosporine concentrations.424 Therefore, it is important that consistent laboratories and methods be used and that the reference ranges for each group of organ transplant recipients and method of assay be known; in addition, any attempt at comparing these ranges with other institutions generally should be limited to circumstances in which the same assay method and therapeutic regimens are employed.424

At present, use of any of the currently available specific immunoassays (RIA, FPIA, FPIA) is acceptable for routine monitoring of whole blood trough cyclosporine concentrations.424 Although use of HPLC also may be appropriate for determining trough cyclosporine concentrations, differences in the results obtained with this assay method relative to immunoassays should be considered when monitoring cyclosporine therapy.46,47,424

Absorption

Following oral administration, cyclosporine is variably and incompletely absorbed.1,2,170,171,391 The 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 the formulation administered.391,425 Absorption of orally administered cyclosporine from conventional (nonmodified) oral formulations reportedly is erratic during long-term therapy.1,170 In hepatic allograft recipients, GI absorption of cyclosporine also may be erratic, especially during the first few weeks of the posttransplantation period because of surgical techniques (e.g., bile duct management with resultant reductions in bile flow) or surgically induced liver dysfunction.12

Peak blood and plasma cyclosporine concentrations occur at about 3.5 hours following oral administration of conventional (nonmodified) formulations of the drug.1 Following oral administration, cyclosporine is metabolized on first pass through the liver.2 Although oral bioavailability of cyclosporine administered as conventional oral formulations averages 30% across various allograft recipients,170,424,425 it exhibits considerable interindividual variation, ranging from 2-89%, depending on numerous variables including organ transplant type;425 in hepatic or renal allograft recipients, estimates range from less than 10% to as high as 89%, respectively.391 Following oral administration of a single 600-mg dose of cyclosporine as a conventional solution in one study, the mean absolute bioavailability was about 30% (range: 10-60%) and a mean peak plasma concentration of about 540 ng/mL (range: 240-1250 ng/mL) was reached at about 3-4 hours.2,8 Limited data indicate that the bioavailability of the conventional liquid-filled capsules of cyclosporine is equivalent to that of the conventional oral solution.170,171,173 In a small number of renal transplant patients who received a mean daily cyclosporine dosage of 3.9 mg/kg (range: 2.2-6.6 mg/kg), given as the conventional oral solution for 1 week followed by the same dosage as the capsules for 1 week, the relative bioavailability of the conventional liquid-filled capsules was 111% (based on the area under the blood concentration-time curve from 0-12 hours) of the oral solution.172 The manufacturer states that peak plasma or blood concentrations of cyclosporine (as determined by HPLC) are approximately 1 or 1.4-2.7 ng/mL per mg of an orally administered dose from a conventional formulation, respectively, in healthy adults.1,70

Although the absolute oral bioavailability of cyclosporine administered as the modified oral formulations (Gengraf^®, Neoral^®) has not been determined in adults, these formulations have greater bioavailability than the conventional (nonmodified) oral formulations of cyclosporine.391,411,412,422,476,477 In addition, while the peak blood or plasma concentration and area under the concentration-time curve (AUC) of cyclosporine increase with the dose administered, with a curvilinear (parabolic) relationship observed at doses between 0-1.4 g of conventional (nonmodified) oral formulations when the biologic fluid used is blood,170,425 the AUC of cyclosporine is linearly related to usual doses of the drug administered as the modified oral formulations;391,422,476,477 a linear relationship also has been described for conventional oral formulations when plasma and HPLC were used.425 Despite the increased AUC and peak blood concentrations of cyclosporine associated with the modified oral formulations, dose-normalized trough concentrations of the drug are similar for both the conventional and modified formulations.391,476,477 The AUC of cyclosporine differed between individuals by a percent coefficient of variation of approximately 20-50% in renal transplant patients administered cyclosporine as the conventional (nonmodified) oral formulation or a modified oral formulation.391,417,476,477 Such a factor makes individualization of dosage necessary for optimal therapy.391 Intraindividual variability in the AUC of cyclosporine and time to peak blood concentration of the drug is reduced with the modified oral formulations compared with the conventional oral formulation.414,417,418,419,476,477 Some evidence indicates that intraindividual variability in peak and trough blood concentrations of cyclosporine also is less with the modified oral formulations.414,417,419 In renal allograft recipients, the percent coefficients of variation within individuals in the AUC of cyclosporine for modified and conventional (nonmodified) oral formulations were 9-21 and 19-26%, respectively.391,414,417,476,477 Intraindividual variabilities in the trough concentration of cyclosporine from modified and conventional oral formulations were 17-30 and 16-38%, respectively, in these patients.391,417,476,477 Limited data in children also show that the bioavailability of cyclosporine is higher with the modified oral formulations.391,476,477 The modified oral capsules of Neoral^® are bioequivalent with Neoral^® oral solution.391,407,414 The modified oral capsules of Gengraf^® also are bioequivalent with the modified oral solution of Gengraf^®.476,477 In addition, the 2 commercially available modified oral formulations of cyclosporine, Neoral^® and Gengraf^®, have been demonstrated to be bioequivalent to each other.480,481,482

The higher bioavailability of the modified oral formulations relative to the conventional (nonmodified) oral formulation varies across patient populations.391,476,477 The mean relative AUC of cyclosporine for a modified oral formulation (Neoral^®) compared with the conventional oral formulation ranged from 1.2-1.5 in crossover studies of stable renal transplant patients.391 In de novo renal transplant patients administered either formulation of cyclosporine, the dose-normalized AUC was 23% greater with the modified oral formulation.391 In de novo hepatic allograft recipients administered either formulation of cyclosporine 28 days after transplantation, the dose-normalized AUC was 50% greater with the modified oral formulation.391,476,477 The absolute oral bioavailability of cyclosporine was 43% (range: 30-68%) from the modified oral formulation compared with 28% (range: 17-42%) from the conventional oral formulation in de novo hepatic transplant patients aged 1.4-10 years old.391,476,477 In a limited number of hepatic allograft recipients with external biliary diversion, the oral bioavailability of cyclosporine was 6.5 times greater with the modified oral formulation (Neoral^®) administered during the first month after transplantation than with the conventional oral formulation.410 In a limited number of cardiac allograft recipients, the AUC of cyclosporine was greater with the modified oral formulation (Neoral^®) relative to the conventional oral formulation.391,415 In a limited number of patients with rheumatoid arthritis, the AUC of cyclosporine was about 20% greater with the modified oral formulation (Neoral^®) compared with the conventional oral formulation.413 Peak blood concentrations are increased by 40-106% in renal transplant patients and by approximately 90% in hepatic transplant patients.391 Peak blood concentrations of cyclosporine occur from 1.5-2 hours following oral administration of the modified formulations to renal transplant patients.391,476,477

Food decreases the AUC and peak blood concentration of cyclosporine attained with the modified oral formulations.391,476,477 In healthy individuals, the AUC and peak blood concentration of cyclosporine were decreased by 15 and 26%, respectively, when the oral formulation of Neoral^® was administered 30 minutes after the start of consumption of a high-fat meal (e.g., 960 calories, 54.4 g of fat).416 In another study, the AUC and peak blood concentration of cyclosporine decreased by 13 and 33%, respectively, when a high-fat meal (e.g., 669 calories, 45 g of fat) was eaten within 30 minutes before administration of this modified oral formulation.391,476,477 Similar effects occurred with a low-fat meal (e.g., 667 calories, 15 g of fat).391,476,477 However, other data have not shown the AUC of cyclosporine from the modified oral formulation of Neoral^® to be affected by a high-fat meal (45 g) or a low-fat meal (15 g).417 Similar discordance of data on the effect of food on cyclosporine absorption with conventional formulations has been described, although high-fat meals and meals given early postoperatively appear most likely to enhance absorption.425

External biliary diversion in de novo hepatic transplant patients had very little effect on the absorption of cyclosporine from the oral formulation of Neoral^®.391,476,477 The change from the trough to the maximal blood concentration of cyclosporine when the T-tube was closed differed by 6.9% from when it was open.391,476,477 In adult de novo renal transplant patients being treated with this modified oral formulation at a dosage of 597 mg (7.95 mg/kg) daily, the AUC over one dosing interval of cyclosporine was 8772 ng •h/mL at 4 weeks.391,476,477 The peak and trough (obtained prior to the morning dose, approximately 12 hours after last dose) blood concentrations of cyclosporine were 1802 and 361 ng/mL, respectively, as determined by specific monoclonal fluorescence polarization immunoassay.391,476,477 In stable adult renal transplant patients being treated with this modified oral formulation at a dosage of 344 mg (4.1 mg/kg) daily, the AUC over one dosing interval was 6035 ng•h/mL.391,476,477 The peak and trough blood concentrations of cyclosporine in these patients were 1333 and 251 ng/mL, respectively, as determined by specific monoclonal fluorescence polarization immunoassay.391,476,477 In adult de novo hepatic transplant patients being treated with this formulation at a dosage of 458 mg (6.9 mg/kg) daily, the AUC over one dosing interval was 7187 ng•h/mL at 4 weeks.391,476,477 The peak and trough blood concentrations of the drug in these patients were 1555 and 268 ng/mL, respectively, as determined by specific monoclonal RIA.391,476,477

In stable hepatic transplant patients 2-8 years of age being treated with the oral formulation of Neoral^® at a dosage of 101 mg (5.95 mg/kg) in 3 divided doses daily, the peak blood concentration of cyclosporine was 629 ng/mL, as determined by specific monoclonal RIA, and the AUC over one dosing interval was 2163 ng•h/mL.391,476,477 In stable hepatic transplant patients 8-15 years of age being treated with this modified formulation at a dosage of 188 mg (4.96 mg/kg) in 2 divided doses daily, the peak blood concentration of the drug was 975 ng/mL, as determined by specific monoclonal RIA, and the AUC over one dosing interval was 4272 ng•h/mL.391,476,477 In a stable hepatic transplant patient 3 years of age being treated with this modified oral formulation at a dosage of 120 mg (8.3 mg/kg) in 2 divided doses daily, the peak blood concentration was 1050 ng/mL, as determined by specific monoclonal fluorescence polarization immunoassay, and the AUC over one dosing interval was 5832 ng•h/mL.391,476,477 In stable hepatic transplant patients 8-15 years of age being treated with this modified formulation at a dosage of 158 mg (5.5 mg/kg) in 2 divided doses daily, the peak blood cyclosporine concentration was 1013 ng/mL, as determined by specific monoclonal fluorescence polarization immunoassay, and the AUC over one dosing interval was 4452 ng•h/mL.391,476,477 In stable renal transplant patients 7-15 years of age being treated with the modified oral formulation at a dosage of 328 mg (7.4 mg/kg) in 2 divided doses daily, the peak blood concentration was 1827 ng/mL, as determined by specific monoclonal fluorescence polarization immunoassay, and the AUC over one dosing interval was 6922 ng•h/mL.391,476,477

Blood or plasma concentrations of cyclosporine required for therapeutic effect or associated with toxicity have not been established precisely.1,2,8,9,10 Organ rejection has reportedly occurred less frequently when trough blood concentrations of the drug (determined by HPLC) were greater than 100 ng/mL.2 Although optimum trough cyclosporine concentrations have not been determined, trough blood or plasma concentrations (i.e., at 24 hours) of 250-800 or 50-300 ng/mL, respectively, as determined by RIA, appear to minimize the frequency of graft rejection and cyclosporine-induced adverse effects.1 An association between trough serum concentrations (determined by RIA) greater than 500 ng/mL and cyclosporine-induced nephrotoxicity has been reported.9

Distribution

Cyclosporine is widely distributed into body fluids and tissues,1,8 with most of the drug being distributed outside the blood volume.391,476,477 Following oral administration of a single 600-mg dose as a conventional formulation in adults with normal renal and hepatic function, the apparent volume of distribution (V_d) of cyclosporine has been reported to be 13 L/kg.2 The drug has a volume of distribution at steady-state (V_ss) of 3-5 L/kg following IV administration in solid organ allograft recipients.2,262,391,425 In one study following IV administration of cyclosporine in patients with severely impaired renal function (i.e., creatinine clearance less than 5 mL/minute), V_ss ranged from 1.45-7.26 L/kg.47

Approximately 90-98% of cyclosporine in plasma is protein bound, mainly to lipoproteins (85-90% of total protein binding).1,2,391,425 Of lipoprotein binding, 43-57% is to high-density lipoproteins (HDLs), 25% to low-density lipoproteins (LDLs), and 2% to very-low-density lipoproteins (VLDLs).425 Distribution of the drug in blood is dose dependent;1,2,391 in vitro in blood, 33-47% of the drug is distributed into plasma, 4-9% into lymphocytes, 4-12% into granulocytes, and 41-58% into erythrocytes.1,70,391,425 At high concentrations, distribution of cyclosporine into leukocytes and erythrocytes becomes saturated.1,391 Concentrations of the drug achieved in mononuclear cells have been reported to be 1000 times greater than those achieved in erythrocytes.425

Cyclosporine crosses the placenta in animals1,75 and humans.75,137,139,425 In a renal allograft recipient who received 450 mg of cyclosporine daily throughout pregnancy, the drug was not present in amniotic fluid at 36 weeks or at amniotomy, but maternal and cord blood concentrations at delivery were 86 and 54 mcg/L, respectively.75

Cyclosporine is distributed into milk.1,139,425 Cyclosporine concentrations in milk reportedly were 101, 109, and 263 mcg/L on the second, third, and fourth days of the postpartum period, respectively, in a patient who received 450 mg of the drug daily throughout pregnancy and the postpartum period.75 Studies in animals have shown that cyclosporine is distributed into milk at a maximum concentration of 2% of the maternal dose.75

Elimination

Blood concentrations of cyclosporine generally appear to decline in a biphasic manner,8,170,391 although a triphasic disposition also has been described.425 In adults with normal renal and hepatic function, the half-life in the initial phase (t_½α) has been reported to average 1.2 hours8 and the half-life in the terminal elimination phase (t_½β) has averaged 8.4-27 hours (range: 4-50 hours).1,8,170,391,424,425 In one study following IV administration of cyclosporine in patients with severely impaired renal function (i.e., creatinine clearance less than 5 mL/minute), t_½β averaged 15.8 or 16.5 hours based on blood cyclosporine concentrations determined by HPLC or RIA, respectively.47

Clearance of cyclosporine from blood following IV administration is approximately 5-7 mL/minute per kg as determined with data (using HPLC) from adult renal or hepatic transplant patients.391 Clearance of the drug in infants may be up to severalfold higher and in older children twice as high as that in adults.391,424,425,426,427,428 Cardiac transplant patients appear to have slightly slower blood cyclosporine clearance.391

The apparent clearance of cyclosporine administered as a modified oral formulation was 593 mL/minute (7.8 mL/minute per kg) after 4 weeks of therapy and 492 mL/minute (5.9 mL/minute per kg) as determined with data (using monoclonal fluorescence polarization immunoassay) from adult de novo renal transplant patients who received a dosage of 597 mg (7.95 mg/kg) daily and from stable adult renal transplant patients who received a dosage of 344 mg (4.1 mg/kg) daily, respectively; after 4 weeks of therapy clearance was 577 mL/minute (8.6 mL/minute per kg) as determined with data (using monoclonal RIA) from de novo hepatic transplant patients who received a dosage of 458 mg (6.89 mg/kg) daily.391,476,477 Limited data are available for pediatric patients.391,424,425,426,427,428 Clearance of cyclosporine from blood averaged 10.6 mL/minute per kg in a study (using specific monoclonal RIA) of renal transplant patients 3-16 years of age administered the drug IV.391 The range in cyclosporine clearance was 9.8-15.5 mL/minute per kg in a study of renal transplant patients 2-16 years old.391 Data (using HPLC) from hepatic transplant patients 0.6-5.6 years of age revealed an average clearance of 9.3 mL/minute per kg.391 The clearance of cyclosporine administered as a modified oral formulation was 285 mL/minute (16.6 mL/minute per kg) or 378 mL/minute (10.2 mL/minute per kg) as determined with data (specific monoclonal RIA used) from stable hepatic transplant patients 2-8 or 8-15 years of age, respectively, who received a dosage of 101 mg (5.95 mg/kg) or 188 mg (4.96 mg/kg) daily, respectively; clearance was 171 mL/minute (11.9 mL/minute per kg) and 328 mL/min (11 mL/minute per kg) as determined with data (using specific monoclonal fluorescence polarization immunoassay) from stable hepatic transplant patients 3 years of age or 8-15 years old, respectively, who received a dosage of 120 mg (8.3 mg/kg) or 158 mg (5.5 mg/kg) daily, respectively.391,476,477 In stable renal transplant patients 7-15 years of age who received cyclosporine as a modified oral formulation at a dosage of 328 mg (7.4 mg/kg) daily, clearance of the drug was 418 mL/minute (8.7 mL/minute per kg) as determined with specific monoclonal fluorescence polarization immunoassay.391,476,477 The clearance of cyclosporine reportedly is not changed substantially by renal failure or dialysis.262,425

Cyclosporine is extensively metabolized in the liver via the cytochrome P-450 enzyme system, principally by the CYP3A isoenzyme, and less extensively in the GI tract and the kidney to at least 30 metabolites found in bile, feces, blood, and urine.391,425 The pharmacologic and toxicologic activities of cyclosporine's metabolites are considerably less than those of the parent drug.83,85,391,424,425 The drug undergoes extensive first-pass metabolism following oral administration.1,2,8,391 Several major metabolic pathways, including hydroxylation of the C_γ-carbon of 2 leucine residues, C_λ-carbon hydroxylation and cyclic ether formation (with oxidation of the double bond) in the side chain of the amino acid 3-hydroxyl- N ,4-dimethyl-l-2-amino-6-octenoic acid, and N -demethylation of N -methyl leucine residues, are involved.1 Conjugation of these metabolites or hydrolysis of the cyclic peptide chain does not appear to be an important pathway for cyclosporine metabolism.1 Oxidation of cyclosporine at its 1-λ, 4- N -desmethylated, and 9-γ positions yields the major metabolites known as AM1 (M17), AM4N (M21), and AM9 (M1), respectively.391,408,424,425 The AUCs at steady state of AM1, AM4N, and AM9 were approximately 70, 7.5, and 21%, respectively, of the blood AUC for cyclosporine in renal transplant patients treated with a conventional oral formulation of the drug.391,408 The manufacturers state that the percentages of a dose present as AM1, AM4N, and AM9 are similar after administration of the conventional (nonmodified) oral formulation or the modified oral formulations, as indicated by blood or biliary concentrations in stable renal or de novo hepatic transplant patients, respectively.391,476,477 In stable renal transplant patients, the ratio of AUC at steady state for AM1 and AM9 to that for cyclosporine did not differ between the conventional oral formulation and the modified oral formulation.409

Cyclosporine is principally excreted via bile, almost entirely as metabolites.1,170,391,425 Only about 6% of a dose of the drug is excreted in urine, with 0.1% of a dose being excreted unchanged.1,170,391,425 However, urinary excretion of unchanged drug may be increased in certain patient populations (e.g., early posttransplant period in bone marrow allograft recipients) and in younger patients.425,426

Chemistry and Stability

Chemistry

Cyclosporine (cyclosporin A) is a cyclosporin immunosuppressive agent produced as a metabolite of the fungus species Aphanocladium album or Beauveria nivea .476,477,478,479 The drug is a nonpolar, cyclic polypeptide antibiotic consisting of 11 amino acids.1,2,65 Cyclosporine is one of several biologically active antibiotics (cyclosporins) produced by these fungi;2,31 cyclosporin A and C are the major metabolites.31

Cyclosporine occurs as a white or essentially white, finely crystalline powder.65 The drug is relatively insoluble in water,3,4 having an aqueous solubility of 0.04 mg/mL at 25°C,70 and is generally soluble in lipids and organic solvents,3,4 having a solubility of more than 80 mg/mL in alcohol at 25°C.70 The potency of cyclosporine is determined on the anhydrous basis; each mcg of cyclosporine is defined as the activity (potency) contained in 1.0173 mcg of the FDA's cyclosporine master standard.65

Commercially available cyclosporine conventional (nonmodified) oral solution has a clear, yellow, oily appearance.5 Cyclosporine conventional oral solution contains the drug in an olive oil and peglicol 5 oleate (Labrafil^® M 1944CS) vehicle with 12.5% (v/v) alcohol.1 Commercially available cyclosporine concentrate for injection occurs as a clear, faintly brownish-yellow solution.5 Cyclosporine concentrate for injection is a sterile solution of the drug in polyoxyl 35 castor oil (Cremophor^® EL, polyethoxylated castor oil) with 32.9% (v/v) alcohol.1,65,71,72 At the time of manufacture, the air in the ampuls of cyclosporine concentrate for injection is replaced with nitrogen.1 The concentrate for injection contains no more than 42 USP endotoxin units per mL.65 Cyclosporine also is commercially available as 25-, 50-, and 100-mg conventional (nonmodified) liquid-filled, soft gelatin capsules.170,171

Cyclosporine also is commercially available as a modified, nonaqueous liquid formulation (Neoral^®) of the drug that immediately forms an emulsion in aqueous fluids; the formulation is available as an oral solution for emulsion and as oral 25- and 100-mg liquid-filled soft gelatin capsules containing the oral solution for emulsion.391,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422 When exposed to an aqueous environment, the oral solution for emulsion forms a homogenous transparent emulsion with a droplet size smaller than 100 nm in diameter;423 as a result, the formulation has been referred to as an oral solution for microemulsion.391,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422 In this formulation, the molecular structure of cyclosporine is unaltered, and aqueous dilution results in formation of an emulsion without reprecipitation of the drug.423 Cyclosporine is dispersed in a mixture of propylene glycol (hydrophilic solvent) and corn oil monoglycerides, diglycerides, and triglycerides (lipophilic solvent); when dispersed, polyoxyl 40 hydrogenated castor oil serves as a surfactant, and d,l-α-tocopherol is present as an antioxidant.391,423 Neoral^® oral solution and liquid-filled capsules also contains dehydrated alcohol in a maximum concentration of 11.9% (v/v).391

In addition, cyclosporine is commercially available as a modified liquid formulation (Gengraf^®) of the drug that forms an aqueous dispersion (also referred to as a microemulsion) of the drug in an aqueous environment; this formulation is available as both an oral solution and as oral 25- and 100-mg liquid-filled capsules.476,477,483 Cyclosporine is dispersed in a mixture of propylene glycol, sorbitan monooleate, and either polyoxyl 40 hydrogenated castor oil (in the oral solution) or polyoxyl 35 castor oil and polyethylene glycol (in the capsules).476,477,483 Gengraf^® liquid-filled capsules also contain alcohol 12.8% (v/v).476

The modified oral formulations of cyclosporine (Neoral^® and Gengraf^®), both as the oral solution and the oral capsules, have increased oral bioavailability compared with the conventional (nonmodified) oral solution and liquid-filled capsules of the drug (i.e., Sandimmune^®).476,477,478,479 Therefore, the conventional (nonmodified) and modified formulations are not bioequivalent and cannot be used interchangeably without appropriate medical supervision.476,477,478,479

Stability

Cyclosporine conventional (nonmodified) oral solution should be stored in the original container at temperature less than 30°C and protected from freezing; refrigeration should be avoided since coalescence and separation of the oral solution could occur.1,107 Opened containers of cyclosporine conventional oral solution must be used within 2 months.1,107,170 Cyclosporine concentrate for injection should be stored at a temperature less than 30°C and protected from freezing and light.1,107 Cyclosporine conventional liquid-filled capsules should be stored in their original unit-dose container at a controlled room temperature of 25°C but may be exposed to temperatures ranging from 15-30°C.479 When stored as directed, the capsules have an expiration date of 3 years from the date of manufacture.170 An odor may be detected when the unit-dose container is opened, which will dissipate shortly thereafter, but this odor does not affect the quality of the preparation.170

Cyclosporine (modified) liquid-filled, soft gelatin capsules (commercially available as Neoral^®) should be stored in their original unit-dose packaging at 20-25°C, and Neoral^® oral solution also should be stored in the original container at 20-25°C.478 At temperatures less than 20°C, Neoral^® oral solution may gel, and light flocculation and/or the formation of a light sediment also may occur; however, such changes do not affect dosing with the syringe provided or efficacy and can be reversed by allowing the solution to warm to a room temperature of 25°C.391 Neoral^® oral solution should not be refrigerated,391 and once opened, containers of the oral solution must be used within 2 months.391

Cyclosporine (modified) liquid-filled capsules commercially available as Gengraf^® should be stored in their original unit-dose packaging at 15-30°C,476 and Gengraf^® oral solution also should be stored in the original container at 15-30°C.477 At temperatures less than 20°C, Gengraf^® oral solution may gel, and light flocculation and/or the formation of a light sediment also may occur; however, such changes do not affect dosing with the syringe provided or efficacy and can be reversed by allowing the solution to warm to a room temperature of 15-30°C.477 Gengraf^® oral solution should not be refrigerated, and once opened, containers of the oral solution must be used within 2 months. 477

Cyclosporine concentrate for injection that has been diluted to a final concentration of approximately 2 mg/mL is stable for 24 hours in 5% dextrose or 0.9% sodium chloride injection in glass or PVC containers.94 Diluted solutions of the drug in 5% dextrose or 0.9% sodium chloride injection do not require protection from light.94,107 There is some evidence that substantial amounts of cyclosporine may be lost during infusion through plastic tubing in IV administration sets.94 Because of combined loss during storage and administration via plastic IV tubing, it has been suggested that dilutions in 0.9% sodium chloride injection be considered stable for no longer than 6 or 12 hours in PVC or glass containers, respectively.94 Polyoxyl 35 castor oil can cause leaching of bis(2-ethylhexyl) phthalate (BEHP, DEHP) from PVC containers1 and, following dilution of cyclosporine concentrate for injection in PVC containers, substantial leaching of DEHP occurs in a time-dependent manner.95 The manufacturer makes no specific recommendations regarding the compatibility of the concentrate for injection with plastic containers; however, to minimize exposure of the patient to leached DEHP, some clinicians recommend that diluted solutions of the drug in PVC containers be administered immediately after preparation.95

Additional Information

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

Preparations ⬆ ⬇

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

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

cycloSPORINE

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

AHFS^® Drug Information. © Copyright, 1959-2024, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 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. [PubMed 6360494]

3. White DJG. Cyclosporin A—clinical pharmacology and therapeutic potential. Drugs . 1982; 24:322-34. [PubMed 6754333]

4. Sheil AGR. Cyclosporin A—a new immune suppressive agent. Med J Aust . 1982; 1:37-9. [PubMed 7038415]

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. [PubMed 328380]

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. [PubMed 7029278]

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. [PubMed 6361559]

10. Burckart GJ. Monitoring cyclosporine therapy. Clin Pharm . 1983; 2:568. [PubMed 6653058]

11. European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet . 1983; 2:986-9. [PubMed 6138592]

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. [PubMed 6126744]

14. Dieperink H, Moller J. Ketoconazole and cyclosporin. Lancet . 1982; 2:1217. [PubMed 6128518]

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. [PubMed 6340275]

16. Canadian Multicentre Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med . 1983; 309:809-15. [PubMed 6350878]

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. [PubMed 6807391]

20. Nagington J, Gray J. Cyclosporin A immunosuppression, Epstein-Barr antibody, and lymphoma. Lancet . 1980; 1:536-7. [PubMed 6102249]

21. Bird AG, McLachlan SM. Cyclosporin A and Epstein-Barr virus. Lancet . 1980; 2:418. [PubMed 6105533]

22. European Multicentre Trial Group. Cyclosporin A as sole immunosuppressive agent in recipients of kidney allografts from cadaver donors. Lancet . 1982; 2:57-60. [PubMed 6123806]

23. Calne RY, Williams R, Lindop M et al. Improved survival after orthotopic liver grafting. BMJ . 1981; 283:115-8. [PubMed 6789932]

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. [PubMed 82837]

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. [PubMed 6101787]

26. Gale RP, Kay HEM, Rimm AA et al. Bone-marrow transplantation for acute leukaemia in first remission. Lancet . 1982; 2:1006-9. [PubMed 6127500]

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. [PubMed 6341839]

28. Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med . 1979; 301:555. [PubMed 460314]

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. [PubMed 91781]

30. Siegl H, Ryffel B. Effect of cyclosporin on renin-angiotensin-aldosterone system. Lancet . 1982; 2:1274. [PubMed 6128567]

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. [PubMed 7041571]

33. Kreis W, Soricelli A. Cyclosporins: immunosuppressive agents with antitumor activity. Experientia . 1979; 35:1506-8. [PubMed 510504]

34. Bueding E, Hawkins J, Cha YN. Antischistosomal effects of cyclosporin A. Agents Actions . 1981; 11:380-3. [PubMed 7282489]

35. Starzl TE, Iwatsuki S, Van Thiel DH et al. Evolution of liver transplantation. Hepatology . 1982; 2:614-36. [PubMed 6749635]

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. [PubMed 6420962]

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. [PubMed 71417,20]

38. Nussenblatt RB, Palestine AG, Rook AH et al. Treatment of intraocular inflammatory disease with cyclosporin A. Lancet . 1983; 2:235-8. [PubMed 6135075]

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. [PubMed 6802949]

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. [PubMed 7022852]

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. [PubMed 6142304]

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. [PubMed 6752020]

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. [PubMed 6627824]

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. [PubMed 6367043]

49. Kahan BD, Wideman CA, Flechner S et al. Anaphylactic reaction to intravenous cyclosporin. Lancet . 1984; 1:52. [PubMed 6140379]

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. [PubMed 21151785]

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. [PubMed 6177219]

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. [PubMed 6849729]

54. Dye D, Watkins J. Suspected anaphylactic reaction to Cremophor^® EL. Br Med J . 1980; 280:1353. [PubMed 7388538]

55. Rolles K, Calne RY. Two cases of benign lumps after treatment with cyclosporin A. Lancet . 1980; 2:795. [PubMed 6107466]

56. Clarke RSJ. Adverse effects of intravenously administered drugs used in anaesthetic practice. Drugs . 1981; 22:26-41. [PubMed 7021121]

57. Gramstad L, Stovner J. Plasma viscosity and Cremophor^®-containing anesthetics. Br J Anaesth . 1979; 51:1175-9. [PubMed 526386]

58. Hüttel MS, Schou OA, Stoffersen E. Complement-mediated reactions to diazepam with Cremophor^® as solvent (Stesolid MR). Br J Anaesth . 1980; 52:77-9. [PubMed 7378233]

59. Lawler PGP, McHutchon A, Bamber PA. Potential hazards of prolonged steroid anaesthesia. Lancet . 1983; 1:1270-1. [PubMed 6134054]

60. Forrest ARW, Watrasiewicz K, Moore CJ. Long term Althesin^® infusion and hyperlipidemia. Br Med J . 1977; 2:1357-8. [PubMed 589210]

61. Niell HB. Miconazole carrier solution, hyperlipidemia, and hematologic problems. N Engl J Med . 1977; 296:1479. [PubMed 865521]

62. Bagnarello AG, Lewis LA, McHenry MC et al. Unusual serum lipoprotein abnormality induced by the vehicle of miconazole. N Engl J Med . 77; 296:497-9.

63. Janssen Pharmaceutica. Monistat i.v.^® prescribing information. In: Huff BB, ed. Physicians' desk reference. 38th ed. Oradell, NJ: Medical Economics Company Inc.; 1984:1025-6.

64. Watkins J, Clark A, Appleyard TN et al. Immune-mediated reactions to Althesin^® (alphaxalone). Br J Anaesth . 1976; 48:881-6. [PubMed 786347]

65. Food and Drug Administration. Antibiotic drugs; cyclosporine. [Docket No. 84N-0105.] Fed Regist . 1984; 49:22631-4.

66. Reviewers' comments (personal observations); 1984 May.

67. Burckart G. Comparison of plasma and serum cyclosporine concentrations. (unpublished observations; 1984 Jun)

68. Starzl TE, Weil R III, Iwatsuki S et al. The use of cyclosporin A and prednisone in cadaver kidney transplantation. Surg Gynecol Obstet . 1980; 151:17-26. [PubMed 6992310]

69. Starzl TE, Hakala TR, Rosenthal JT et al. Variable convalescence and therapy after cadaveric renal transplantation under cyclosporin A and steroids. Surg Gynecol Obstet . 1982; 154:819-25. [PubMed 7043758]

70. Oryshkevich B (Sandoz, Inc, East Hanover, NJ): Personal communication; 1984 Jun.

71. Tuman W (BASF Wyandotte Corporation, Wyandotte, MI): Personal communication; 1984 Jun 12.

72. Timer E (USP, Rockville, MD): Personal communication; 1984 Jun 13.

73. Wallwork J, McGregor CGA, Wells FC et al. Cyclosporin and intravenous sulphadimidine and trimethoprim therapy. Lancet . 1983; 1:366-7. [PubMed 6130373]

74. Joss DV, Barrett AJ, Kendra JR et al. Hypertension and convulsions in children receiving cyclosporin A. Lancet . 1982; 1:906. [PubMed 6122119]

75. Lewis GJ, Lamont CAR, Lee HA et al. Successful pregnancy in a renal transplant recipient taking cyclosporin A. BMJ . 1983; 286:603. [PubMed 6402165]

76. Bennett WM, Pulliam JP. Cyclosporine nephrotoxicity. Ann Intern Med . 1983; 99:851-4. [PubMed 6360003]

77. Ost L. Effects of cyclosporin on prednisolone metabolism. Lancet . 1984; 1:451. [PubMed 6142174]

78. Klintmalm G, Sawe J. High dose methylprednisolone increases plasma cyclosporin levels in renal transplant recipients. Lancet . 1984; 1:731. [PubMed 6143058]

79. Gosselin RE, Hodge HC, Smith RP et al. Clinical toxicology of commercial products. Acute poisoning. 5th ed. Baltimore: The Williams & Wilkins Co; 1984:I-10.

80. Niederberger W, Lemaire M, Maurer G et al. Distribution and binding of cyclosporine in blood and tissues. In: Kahan BD, ed. Cyclosporine: biological activity and clinical applications. Orlando, FL: Grune & Stratton, Inc; 1984:203-5.

81. Stiller CR. Update for the Canadian Multicentre Trial of cyclosporine in renal allografts. N Engl J Med . 1984; 310:1464-5. [PubMed 6371537]

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

83. Schran HF, Abisch E. Monitoring of cyclosporine: a status report. Ther Drug Monit . (in press)

84. Robinson CA, Jr, Ketchum CH. Monitoring of cyclosporin A: is it possible? Ther Drug Monit . 1983; 5:371-2. Letter.

85. Ferguson RM, Fidelus-Gort R. The immunosuppressive action of cyclosporine in man. In: Kahan BD, ed. Cyclosporine: biological activity and clinical applications. Orlando, FL: Grune & Stratton, Inc; 1984:134-40.

86. Bia MJ, Flye W. Lymphoma and cyclosporin. Lancet . 1984; 1:1408. [PubMed 6145856]

87. Varghese Z, Chan MK, Steele LV et al. How to measure cyclosporin. Lancet . 1984; 1:1407-8. [PubMed 6145855]

88. Petersen KC, Silberman H, Berne TV. Hyperkalaemia after cyclosporin therapy. Lancet . 1984; 1:1470. [PubMed 6145908]

89. Cho SI, Bradley JW, Monaco AP et al. Comparison of kidney transplant survival between patients treated with cyclosporine and those treated with azathioprine and antithymocyte globulin. Am J Surg . 1984; 147:518-23. [PubMed 6370008]

90. Reviewers' comments on Lymphocyte Immune Globulin, Antithymocyte Globulin (Equine) 92:44 (personal observations); 1985 Mar.

91. Halloran PF, Lien J, Aprile M et al. Preliminary results of a randomized comparison of cyclosporine and Minnesota antilymphoblast globulin. Transplant Proc . 1982; 14:627-30. [PubMed 6301117]

92. Najarian JS, Fryd DS, Strand M et al. A single institution, randomized, prospective trial of cyclosporine versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients. Ann Surg . 1985; 201:142-57. [PubMed 3882063]

93. Hall BM, Tiller DJ, Horvath JS et al. Treatment of renal transplantation rejection: cyclosporin A versus conventional treatment with azathioprine, prednisone and antithymocyte immunoglobulin in primary cadaveric renal transplantation. Med J Aust . 1985; 142:179-85. [PubMed 3881654]

94. Ptachcinski RJ, Logue LW, Burckart GJ et al. Stability and availability of cyclosporine in 5% dextrose injection or 0.9% sodium chloride injection. Am J Hosp Pharm . 1986; 43:94-7. [PubMed 3953588]

95. Venkataramanan R, Burckart GJ, Ptachcinski RJ et al. Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous cyclosporine solution. Am J Hosp Pharm . 1986; 43:2800-2. [PubMed 3799618]

96. Canadian Multicentre Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation: analysis at three years. N Engl J Med . 1986; 314:1219-25. [PubMed 2871486]

97. Deeg HJ, Storb R, Thomas ED et al. Cyclosporine as prophylaxis for graft-versus-host disease: a randomized study in patients undergoing marrow transplantation for acute nonlymphoblastic leukemia. Blood . 1985; 65:1325-34. [PubMed 3888312]

98. Storb R, Deeg HJ, Thomas ED et al. Marrow transplantation for chronic myelocytic leukemia: a controlled trial of cyclosporine versus methotrexate for prophylaxis of graft-versus-host disease. Blood . 1985; 66:698-702. [PubMed 2862933]

99. Irle C, Deeg HJ, Buckner CD et al. Marrow transplantation for leukemia following fractionated total body irradiation: a comparative trial of methotrexate and cyclosporine. Leuk Res . 1985; 9:1255-61. [PubMed 3906282]

100. Storb R, Deeg HJ, Whitehead J et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med . 1986; 314:729-25. [PubMed 3513012]

101. Tutschka PJ, Hess AD, Beschorner WE et al. Cyclosporine in clinical marrow transplantation: the Baltimore experience. Transplant Proc . 1983; 15:2613-6. [PubMed 6364508]

102. Kennedy MS, Deeg HJ, Storb R et al. Treatment of acute graft-vs-host disease after allogeneic marrow transplantation: randomized study comparing corticosteroids and cyclosporine. Am J Med . 1985; 78:978-83. [PubMed 3893112]

103. Neudorf S, Filipovich A, Ramsay N et al. Prevention and treatment of acute graft-versus-host disease. Semin Hematol . 1984; 21:91-100. [PubMed 6377502]

104. Velu T, Debusscher L, Stryckmans PA. Cyclosporin-associated fatal convulsions. Lancet . 1985; 1:219. [PubMed 2857288]

105. Beaman M, Parvin S, Veitch PS et al. Convulsions associated with cyclosporin A in renal transplant recipients. BMJ . 1985; 290:139-40. [PubMed 3917716]

106. Thompson CR, June CH, Sullivan KM et al. Association between cyclosporin neurotoxicity and hypomagnesaemia. Lancet . 1984; 2:1116-20. [PubMed 6150182]

107. Sandoz Pharmaceuticals. Sandimmune^® (cyclosporine) practical guide. East Hanover, NJ; 1985 Sep. SDI-103.

108. Hanto DW, Gajl-Peczalska KJ, Frizzera G et al. Epstein-Barr virus (EBV) induced polyclonal and monoclonal B-cell lymphoproliferative diseases occurring after renal transplantation: clinical, pathologic, and virologic findings and implications for therapy. Ann Surg . 1983; 198:356-69. [PubMed 6311121]

109. Shepard JH, Canafax DM, Simmons RL et al. Cyclosporine-ketoconazole: a potentially dangerous drug-drug interaction. Clin Pharm . 1986; 5:468. [PubMed 3720214]

110. Daneshmend TK. Ketoconazole-cyclosporin interaction. Lancet . 1982; 2:1342-3. [PubMed 6128627]

111. Anon. Ketoconazole (Nizoral) interactions. Drug Interact Newsl . 1986; 6(10):U19-20.

112. Langhoff E, Madsen S. Rapid metabolism of cyclosporin and prednisone in kidney transplant patient receiving tuberculostatic treatment. Lancet . 1983; 2:1031. [PubMed 6138578]

113. Daniels NJ, Dover JS, Schachter RK. Interaction between cyclosporin and rifampicin. Lancet . 1984; 2:639. [PubMed 6147671]

114. Allen RDM, Hunnisett AG, Morris PJ. Cyclosporin and rifampicin in renal transplantation. Lancet . 1985; 1:980. [PubMed 2859432]

115. Coward RA, Raftery AT, Brown CB. Cyclosporin and antituberculous therapy. Lancet . 1985; 1:1342-3.

116. Howard P, Bixler TJ, Gill B. Cyclosporine-rifampin drug interaction. Drug Intell Clin Pharm . 1985; 19:763-4. [PubMed 4053986]

117. Keown PA, Stiller CR, Laupacis AL et al. The effects and side effects of cyclosporine: relationship to drug pharmacokinetics. Transplant Proc . 1982; 14:659-61. [PubMed 6762722]

118. Keown PA, Laupacis A, Carruthers G et al. Interaction between phenytoin and cyclosporine following organ transplantation. Transplantation . 1984; 38:304-6. [PubMed 6474556]

119. Freeman DJ, Laupacis A, Keown PA et al. Evaluation of cyclosporin-phenytoin interaction with observations on cyclosporin metabolites. Br J Clin Pharmacol . 1984; 18:887-93. [PubMed 6529529]

120. Ptachcinski RJ, Carpenter BJ, Burckart GJ et al. Effect of erythromycin on cyclosporine levels. N Engl J Med . 1985; 313:1416-7. [PubMed 4058537]

121. Kohan DE. Possible interaction between cyclosporine and erythromycin. N Engl J Med . 1986; 314:448. [PubMed 3511381]

122. Martel R, Heinrichs D, Stiller CR et al. The effects of erythromycin in patients treated with cyclosporine. Ann Intern Med . 1986; 104:660-1. [PubMed 3963664]

123. Godin JRP, Sketris IS, Belitsky P. Erythromycin-cyclosporine interaction. Drug Intell Clin Pharm . 1986; 20:504-5. [PubMed 3522164]

124. Freeman DJ, Martell R, Carruthers SG et al. The effect of erythromycin on the pharmacokinetics of cyclosporine. Clin Pharmacol Ther . 1986; 39:193.

125. Anon. Erythromycin interactions. Drug Interact Newsl . 1986; 6:U11-2.

126. Pochet JM, Pirson Y. Cyclosporin-diltiazem interaction. Lancet . 1986; 1:979. [PubMed 2871278]

127. Grino JM, Sabate I, Castelao AM et al. Influence of diltiazem on cyclosporin clearance. Lancet . 1986; 1:1387. [PubMed 2872500]

128. Moody H, Matz L, Hurst P. Vascular lesions as manifestations of cyclosporin nephrotoxicity. Lancet . 1986; 1:1221-2. [PubMed 2871465]

129. Cohen DJ, Loertscher R, Rubin MF et al. Cyclosporine: a new immunosuppressive agent for organ transplantation. Ann Intern Med . 1984; 101:667-82. [PubMed 6385799]

130. Durrant S, Chipping PM, Palmer S et al. Cyclosporin A, methylprednisolone, and convulsions. Lancet . 1982; 1:906.

131. Boogaerts MA, Zachee P, Verwilghen RL. Cyclosporin, methylprednisolone, and convulsions. Lancet . 1982; 2:1216-7. [PubMed 6128517]

132. Scott JP, Higenbottam TW. Adverse reactions and interactions of cyclosporin. Med Toxicol Adverse Drug Exp . 1988; 3:107-27. [PubMed 3287088]

133. Samuel KSS, Najarian JS, Nevins TE et al. Low-dose cyclosporine therapy combined with standard immunosuppression in pediatric renal transplantation. J Pediatr . 1987; 111(6 Part 2):1017-21. [PubMed 3316573]

134. Lin HY, Rocher LL, McQuillan MA et al. Cyclosporine-induced hyperuricemia and gout. N Engl J Med . 1989; 321:287-92. [PubMed 2664517]

135. Ballantyne CM, Podet EJ, Patsch WP et al. Effects of cyclosporine therapy on plasma lipoprotein levels. JAMA . 1989; 262:53-6. [PubMed 2733125]

136. Barton CH, Vaziri ND, Martin DC et al. Hypomagnesemia and renal magnesium wasting in renal transplant recipients receiving cyclosporine. Am J Med . 1987; 83:693-9. [PubMed 3314493]

137. Pickrell MD, Sawers R, Michael J. Pregnancy after renal transplantation: severe intrauterine growth retardation during treatment with cyclosporin A. BMJ . 1988; 296:825. [PubMed 3130929]

138. de Groen PC, Aksamit AJ, Rakela J et al. Central nervous system toxicity after liver transplantation: the role of cyclosporine and cholesterol. N Engl J Med . 1987; 317:861-6. [PubMed 3306386]

139. Klintmalm G, Althoff P, Appleby G et al. Renal function in a newborn baby delivered of a renal transplant patient taking cyclosporine. Transplantation . 1984; 38:198-9. [PubMed 6380049]

140. Stahl RAK, Kanz L, Maier B et al. Hyperchloremic metabolic acidosis with high serum potassium in renal transplant recipients: a cyclosporine A associated side effect. Clin Nephrol . 1986; 25:245-8. [PubMed 3521998]

141. Hamilton DV, Evans DB, Thiru S. Toxicity of cyclosporin A in organ grafting. In: Cyclosporin A: proceedings of an International Conference on Cyclosporin. New York: Elsevier Biomedical Press; 1981:393-410.

142. Hamilton DV, Evans DB, Henderson RG et al. “Nephrotoxicity” and metabolic acidosis in transplant patients on cyclosporin A. Proc Eur Dial Transplant Assoc . 1981; 18:400-7. [PubMed 7036160]

143. Adu D, Michael J, Turney J et al. Hyperkalemia in cyclosporin-treated renal allograft recipients. Lancet . 1983; 2:370-2. [PubMed 6135874]

144. Thompson CB, June CH, Sullivan KM et al. Association between cyclosporin neurotoxicity and hypomagnesaemia. Lancet . 1984; 2:1116-20. [PubMed 6150182]

145. June CH, Thompson CB, Kennedy MS et al. Profound hypomagnesemia and renal magnesium wasting associated with the use of cyclosporine for marrow transplantation. Transplantation . 1985; 39:620-4. [PubMed 3890292]

146. Cohen SL, Boner G, Rosenfeld JB et al. The mechanism of hyperuricaemia in cyclosporine-treated renal transplant recipients. Transplant Proc . 1987; 19:1829-30. [PubMed 3079042]

147. Chapman JR, Griffiths D, Harding NGL et al. Reversibility of cyclosporin nephrotoxicity after three months' treatment. Lancet . 1985; 1:128-30. [PubMed 2857212]

148. Tiller DJ, Hall BM, Horvarth JS et al. Gout and hyperuricaemia in patients on cyclosporin and diuretics. Lancet . 1985; 1:453. [PubMed 2857822]

149. Leunissen KML, Bosman F, van Hooff JP. Cyclosporin, uric acid, and the kidney. Lancet . 1985; 1:702.

150. Loughran TP Jr, Deeg HJ, Dahlberg S et al. Incidence of hypertension after marrow transplantation among 112 patients randomized to either cyclosporine or methotrexate as graft-versus-host disease prophylaxis. Br J Haematol . 1985; 59:547-53. [PubMed 3882141]

151. Weidle PJ, Vlasses PH. Systemic hypertension associated with cyclosporine: a review. Drug Intell Clin Pharm . 1988; 22:443-51. [PubMed 3293956]

152. Thompson ME, Shapiro AP, Johnsen AM et al. The contrasting effects of cyclosporin-A and azathioprine on arterial blood pressure and renal function following cardiac transplantation. Int J Cardiol . 1986; 11:219-29. [PubMed 3519476]

153. Rubin AM, Kang H. Cerebral blindness and encephalopathy with cyclosporin A toxicity. Neurology . 1987; 37:1072-6. [PubMed 3587633]

154. Adams DH, Ponsford S, Gunson B et al. Neurological complications following liver transplantation. Lancet . 1987; 1:949-51. [PubMed 2882342]

155. Berden JHM, Hoitsma AJ, Merx JL et al. Severe central nervous system toxicity associated with cyclosporin. Lancet . 1985; 1:219-20. [PubMed 2857289]

156. Oyer PE, Stinson EB, Jamieson SW et al. Cyclosporine in cardiac transplantation: a 2½ year follow-up. Transplant Proc . 1983; 15:246-52.

157. Bennett WM, Porter GA. Cyclosporine-associated hypertension. Am J Med . 1988; 85:131-3. [PubMed 3400689]

158. Curtis JJ, Luke RG, Jones P. Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent. Am J Med . 1988; 85:134-8. [PubMed 3041828]

159. Sennesael JJ, Dupont AG, Verbeelen DL et al. Hypertension and cyclosporine. Ann Intern Med . 1986; 104:729. [PubMed 3754408]

160. Mordy DL, Oyer PE, Jamieson SW et al. Cyclosporine in heart and heart-lung transplantation. Can J Surg . 1985; 28:274-82. [PubMed 3922606]

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

162. European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet . 1983; 2:986-9. [PubMed 6138592]

163. Atkinson K, Biggs J, Darveniza P et al. Cyclosporin-associated central nervous system toxicity after allogenic bone marrow transplantation. Transplantation . 1984; 38:34-7. [PubMed 6377609]

164. Joss DV, Barrett AJ, Kendra JR et al. Hypertension and convulsions in children receiving cyclosporin A. Lancet . 1982; 1:906. [PubMed 6122119]

165. Beaman M, Parvin S, Veitch PS et al. Convulsions associated with cyclosporin A in renal transplant recipients. BMJ . 1985; 290:139-40. [PubMed 3917716]

166. Laupacis A. Complications of cyclosporin therapy—a comparison to azathioprine. Transplant Proc . 1983; 15:2748-53.

167. Foley RJ, Van Buren CT, Hamner R et al. Cyclosporin-associated hyperkalemia. Transplant Proc . 1983; 15:2726-9.

168. Geigy. Voltaren^® prescribing information. Ardsley, NY; 1988 Jul.

169. Deray G, Le Hoang P, Aupetit B et al. Enhancement of cyclosporine A nephrotoxicity by diclofenac. Clin Nephrol . 1987; 27:213-4. [PubMed 2953512]

170. Sandoz Pharmaceuticals. Sandimmune^® (cyclosporine) soft gelatin capsules oral solution, and concentrate for injection prescribing information. East Hanover, NJ; 1991 Jul 15.

171. Sandoz Pharmaceuticals. Sandimmune^® (cyclosporine) soft gelatin capsules pharmacy fact sheet. East Hanover, NJ; 1990 Mar.

172. Zehnder C, Beveridge T, Nüesch E et al. Cyclosporine A capsules: bioavailability and clinical acceptance study in renal transplant patients. Transplant Proc . 1988; 20(Suppl 2):641-3. [PubMed 3284114]

173. Bleck JS, Nashan B, Christians U et al. Single dose pharmacokinetics of ciclosporin and its main metabolites after oral ciclosporin as oily solution or capsule. Arzneimittelforschung . 1990; 40:62-4. [PubMed 2340002]

174. Upjohn Co. Depo-Medrol^® (methylprednisolone acetate) sterile aqueous suspension and sterile suspension prescribing information. In: Barnhart ER, publisher. Physicians' desk reference. 45th ed. Oradell, NJ: Medical Economics Company Inc.; 1991(Suppl A):A72.

175. Upjohn Co. Solu-Medrol^® (methylprednisolone sodium succinate) sterile powder and for injection prescribing information. In: Barnhart ER, publisher. Physicians' desk reference. 45th ed. Oradell, NJ: Medical Economics Company Inc.; 1991(Suppl A):A73.

176. Upjohn Co. Medrol^® (methylprednisolone) tablets prescribing information. In: Barnhart ER, publisher. Physicians' desk reference. 45th ed. Oradell, NJ: Medical Economics Company Inc.; 1991(Suppl A):A73.

177. Lichtiger S, Present DH, Kornbluth A et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med . 1994; 330:1841-5. [PubMed 8196726]

178. Sartor RB. Cyclosporine therapy for inflammatory bowel disease. N Engl J Med . 1994; 330:1897-8. [PubMed 8196735]

179. Treem WR, Hyams JS. Cyclosporine therapy for gastrointestinal disease. J Pediatr Gastroenterol Nutr . 1994; 18:270-8. [PubMed 8057207]

180. Allgayer H, Seitz KH, Gugler R. Can cyclosporin prevent proctocolectomy in severe steroid-refractory ulcerative colitis? Lessons from a case report. Dig Dis Sci . 1993; 38:380-2. [PubMed 8425455]

181. Brynskov J. Cyclosporin for inflammatory bowel disease: mechanisms and possible actions. Scand J Gastroenterol . 1993; 28:849-57. [PubMed 8266013]

182. Sandborn WJ, Tremaine WJ. Cyclosporine treatment of inflammatory bowel disease. Mayo Clin Proc . 1992; 67:981-90. [PubMed 1434859]

183. Sandborn WJ, Goldman DH, Lawson GM et al. Measurement of colonic tissue cyclosporine concentration in children with severe ulcerative colitis. J Pediatr Gastroenterol Nutr . 1992; 15:125-9. [PubMed 1357126]

184. Treem WR, Davis PM, Hyams JS. Cyclosporine treatment of severe ulcerative colitis in children. J Pediatr . 1991; 119:994-7. [PubMed 1960626]

185. Lichtiger S, Present DH. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis. Lancet . 1990; 336:16-9. [PubMed 1973211]

186. Porro GB, Petrillo M, Ardizzone S. Cyclosporin treatment for severe active ulcerative colitis. Lancet . 1990; 336:439. [PubMed 1974964]

187. Stange EF, Fleig WE, Rehklau E et al. Cyclosporin A treatment in inflammatory bowel disease. Dig Dis Sci . 1989; 34:1387-92. [PubMed 2766906]

188. Van Thiel DH. Cyclosporine and inflammatory bowel disease. Dig Dis Sci . 1989; 34:1817-9. [PubMed 2598750]

189. Hyams JS, Treem WR. Cyclosporine treatment of fulminant colitis. J Pediatr Gastroenterol Nutr . 1989; 9:383-7. [PubMed 2614627]

190. Gupta S, Keshavarzian A, Hodgson HJF. Cyclosporin in ulcerative colitis. Lancet . 1984; 2:1277-8. [PubMed 6150306]

191. Sandborn WJ, Wiesner RH, Tremaine WJ et al. Ulcerative colitis disease activity following treatment of associated primary sclerosing cholangitis with cyclosporin. Gut . 1993; 34:242-6. [PubMed 8432481]

192. Ferzoco SJ, Becker JM. Does aggressive medical therapy for acute ulcerative colitis result in a higher incidence of staged colectomy? Arch Surg . 1994; 129:420-4. (IDIS 327639)

193. Winter TA, Dalton HR, Merrett MN et al. Cyclosporin A retention enemas in refractory distal ulcerative colitis and “pouchitis.” Scand J Gastroenterol . 1993; 28:701-4. (IDIS 319335)

194. Brynskov J, Freund L, Thomsen OO et al. Treatment of refractory ulcerative colitis with cyclosporin enemas. Lancet . 1989; 1:721-2. [PubMed 2564527]

195. Ranzi T, Campanini MC, Velio P et al. Treatment of chronic proctosigmoiditis with cyclosporin enemas. Lancet . 1989; 2:97. [PubMed 2567886]

196. Sandborn WJ, Tremaine WJ, Schroeder KW et al. A placebo-controlled trial of cyclosporine enemas for mildly to moderately active left-sided ulcerative colitis. Gastroenterology . 1994; 106:1429-35. [PubMed 8194687]

197. Sandborn WJ, Tremaine WJ, Schroeder KW et al. Cyclosporine enemas for treatment-resistant, mildly to moderately active, left-sided ulcerative colitis. Am J Gastroenterol . 1993; 88:640-6. [PubMed 8480724]

198. Present DH. Cyclosporine and other immunosuppressive agents: current and future role in the treatment of inflammatory bowel disease. Am J Gastroenterol . 1993; 88:627-9. [PubMed 8480721]

199. Brynskov J, Freund L, Rasmussen SN et al. A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn's disease. N Engl J Med . 1989; 321:845-50. [PubMed 2671739]

200. Sachar DB. Cyclosporine treatment for inflammatory bowel disease: a step backward or a leap forward? N Engl J Med . 1989; 321:894-6. Editorial.

201. Lobo AJ, Juby LD, Axon ATR. Cyclosporine in Crohn's disease. N Engl J Med . 1990; 322:636. [PubMed 2406605]

202. Feagan BG, Archambault A, Fedorak R et al. Cyclosporine in Crohn's disease. N Engl J Med . 1990; 322:636-7. [PubMed 2406605]

203. Brynskov J, Binder V, Riis P. Cyclosporine in Crohn's disease. N Engl J Med . 1990; 322:637. [PubMed 2304516]

204. Sachar DB. Cyclosporine in Crohn's disease. N Engl J Med . 1990; 322:637. [PubMed 2304516]

205. Ardizzone S, Fasoli R, Sangaletti O et al. The treatment of chronically active Crohn's disease with cyclosporin A: a preliminary report. Curr Ther Res . 1990; 48:1-4.

206. Ranzi T, Campanini MC, Di Palo FQ et al. Cyclosporin A in Crohn's disease. Curr Ther Res . 1989; 45:245-52.

207. Löfberg R, Angelin B, Einarsson K et al. Unsatisfactory effect of cyclosporin A treatment in Crohn's disease: a report of five cases. J Intern Med . 1989; 226:157-61. [PubMed 2677208]

208. Allam BF, Tillman JE, Thomson TJ et al. Effective intravenous cyclosporin therapy in a patient with severe Crohn's disease on parenteral nutrition. Gut . 1987; 28:1166-9. [PubMed 3119435]

209. Allison MC, Pounder RE. Cyclosporin for Crohn's disease. Lancet . 1984; 1:902-3. [PubMed 6143202]

210. Brynskov J, Freund L, Rasmussen SN et al. Final report on a placebo-controlled, double-blind, randomized, multicentre trial of cyclosporin treatment in active chronic Crohn's disease. Scand J Gastroenterol . 1991; 26:689-95. [PubMed 1896809]

211. Feagan BG, McDonald JWD, Rochon J et al. Low-dose cyclosporine for the treatment of Crohn's disease. N Engl J Med . 1994; 330:1846-51. [PubMed 8196727]

212. Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn's disease. Dig Dis Sci . 1994; 39:374-80. [PubMed 8313821]

213. Hanauer SB, Smith MB. Rapid closure of Crohn's disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol . 1993; 88:646-9. [PubMed 8480725]

214. Sanderson IR, Phillips AD, Spencer J et al. Response to autoimmune enteropathy to cyclosporin A therapy. Gut . 1991; 32:1421-5. [PubMed 1752480]

215. Seidman EG, Lacaille F, Russo P et al. Successful treatment of autoimmune enteropathy with cyclosporine. J Pediatr . 1990; 117:929-32. [PubMed 2246696]

216. Coulthard M, Searle J, Patrick M et al. Cyclosporin-responsive enteropathy and protracted diarrhea. J Pediatr Gastroenterol Nutr . 1990; 10:257-61. [PubMed 2303980]

217. Bernstein EF, Whitington PF. Successful treatment of atypical sprue in an infant with cyclosporine. Gastroenterology . 1988; 95:199-204. [PubMed 3371614]

218. Longstreth GF. Successful treatment of refractory sprue with cyclosporine. Ann Intern Med . 1993; 119:1014-6. [PubMed 8214978]

219. Lombard M, Portmann B, Neuberger J et al. Cyclosporin A treatment in primary biliary cirrhosis: results of a long-term placebo controlled trial. Gastroenterology . 1993; 104:519-26. [PubMed 8425695]

220. Wiesner RH, Ludwig J, Lindor KD et al. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med . 322:1419-24.

221. Minuk GY, Bohme CE, Burgess E et al. Pilot study of cyclosporin A in patients with symptomatic primary biliary cirrhosis. Gastroenterology . 1988; 95:1356-63. [PubMed 3169499]

222. Routhier G, Epstein O, Janossy G et al. Effects of cyclosporin A on suppressor and induced T lymphocytes in primary biliary cirrhosis. Lancet . 1980; 2:1223-6. [PubMed 6108396]

223. Munoz SJ. Cyclosporine in primary biliary cirrhosis. N Engl J Med . 1990; 323:1352. [PubMed 2215626]

224. Laburte C, Grossman R, Abi-Rached J et al. Efficacy and safety of oral cyclosporin A (CyA; Sandimmun^®) for long-term treatment of chronic severe plaque psoriasis. Br J Dermatol . 1994; 130:366-75. [PubMed 8148280]

225. Ellis CN, Fradin MS, Messana JM et al. Cyclosporine for plaque-type psoriasis. N Engl J Med . 1991; 324:277-84. [PubMed 1986287]

226. Lowe NJ. Systemic treatment of severe psoriasis: the role of cyclosporine. N Engl J Med . 1991; 324:333-4. [PubMed 1986292]

227. Rapaport M. Cyclosporine for treatment of psoriasis. N Engl J Med . 1991; 324:1894. [PubMed 2041556]

228. Ellis CN, Fradin MS, Brown MD et al. Cyclosporine for treatment of psoriasis. N Engl J Med . 1991; 324:1895. [PubMed 1645846]

229. Meinardi MMH, De Rie MA, Bos JD. Oral cyclosporin A in the treatment of psoriasis: an overview of studies performed in The Netherlands. Br J Dermatol . 1990; 122(Suppl 36):27-31. [PubMed 2196081]

230. Powles AV, Baker BS, Valdimarsson H et al. Four years of experience with cyclosporin A for psoriasis. Br J Dermatol . 1990; 122(Suppl 36):13-9. [PubMed 2369568]

231. Timonen P, Friend D, Abeywickrama K et al. Efficacy of low-dose cyclosporin A in psoriasis: results of dose-finding studies. Br J Dermatol . 1990; 122(Suppl 36):33-9. [PubMed 2196082]

232. Fradin MS, Ellis CN, Voorhees JJ. Efficacy of cyclosporin A in psoriasis: a summary of the United States' experience. Br J Dermatol . 1990; 122(Suppl 36):21-5. [PubMed 2196080]

233. Griffiths CEM, Powles AV, McFadden J et al. Long-term cyclosporin for psoriasis. Br J Dermatol . 1989; 120:253-60. [PubMed 2923798]

234. Van Joost T, Bos JD, Heule F et al. Low-dose cyclosporin A in severe psoriasis: a double-blind study. Br J Dermatol . 1988; 118:183-90. [PubMed 3280000]

235. Wentzell JM, Baughman RD, O'Connor GT et al. Cyclosporine in the treatment of psoriasis. Arch Dermatol . 1987; 123:163-5. [PubMed 3813586]

236. Ellis CN, Gorsulowsky DC, Hamilton TA et al. Cyclosporine improves psoriasis in a double-blind study. JAMA . 1986; 256:3110-6. [PubMed 3023712]

237. Brookes DB. Clearance of psoriasis with low dose cyclosporin. BMJ . 1986; 293:1098-9. [PubMed 3094789]

238. Griffiths CEM, Powles AV, Leonard JN et al. Clearance of psoriasis with low dose cyclosporin. BMJ . 1986; 293:731-2. [PubMed 3094629]

239. Marks JM. Cyclosporin A treatment of severe psoriasis. Br J Dermatol . 1986; 115:745-6. [PubMed 3542010]

240. Marks J. Psoriasis. BMJ . 1986; 293:509. [PubMed 3091187]

241. Van Joost T, Huele F, Stolz E et al. Short-term use of cyclosporin A in severe psoriasis. Br J Dermatol . 1986; 114:615-20. [PubMed 3718852]

242. van Hoofe JP, Leunissen KML, Staak W. Cyclosporin and psoriasis. Lancet . 1985; 1:335.

243. Harper JI, Keat ACS, Staughton RCD. Cyclosporin for psoriasis. Lancet . 1984; 2:981-2.

244. Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med . 1979; 301:555. [PubMed 460314]

245. Cacoub P, Artru L, Canesi M J et al. Life-threatening psoriasis relapse on withdrawal of cyclosporin. Lancet . 1988; 2:219-20.

246. Powles AV, Baker BS, McFadden et al. Psoriasis and cyclosporin withdrawal. Lancet . 1988; 2:513. [PubMed 2900438]

247. Burnes MK, Ellis CN, Eisen D et al. Intralesional cyclosporine for psoriasis. Arch Dermatol . 1992; 128:786-90. [PubMed 1599264]

248. Powles AV, Baker BS, McFadden J et al. Intralesional injection of cyclosporin in psoriasis. Lancet . 1988; 1:537. [PubMed 2893957]

249. Mizoguchi M, Kawaguchi K, Ohsuga Y et al. Cyclosporin ointment for psoriasis and atopic dermatitis. Lancet . 1992; 339:1120. [PubMed 1349141]

250. Schulze HJ, Mahrle G, Stiegleder GK. Topical cyclosporin A in psoriasis. Br J Dermatol . 1990; 122:113-4. [PubMed 2297498]

251. Griffiths CEM, Powles AV, Baker BS et al. Topical cyclosporin and psoriasis. Lancet . 1987; 1:806. [PubMed 2882209]

252. Thomson AW, Sewell HF, Aldridge RD. Topical cyclosporin and immunologically- mediated skin disorders. Lancet . 1987; 1:1212. [PubMed 2883531]

253. Petzelbauer P, Hönigsmann H, Langer K et al. Cyclosporin A in combination with photochemotherapy (PUVA) in the treatment of psoriasis. Br J Dermatol . 1990; 123:641- 7. [PubMed 2248892]

254. Brechtel B, Wellenreuther U, Toppe E et al. Combination of etretinate with cyclosporine in the treatment of severe recalcitrant psoriasis. J Am Acad Dermatol . 1994; 30:1023-4. [PubMed 8188867]

255. Meinardi MMH, Westerhof W, Bos JD. Generalized pustular psoriasis (von Zumbusch) responding to cyclosporin A. Br J Dermatol . 1987; 116:269-70. [PubMed 3828221]

256. Arnold WP, Gerritsen MJP, Van de Kerkof PCM. Response of nail psoriasis to cyclosporin. Br J Dermatol . 1993; 129:750-1. [PubMed 8286269]

257. Reitamo S, Erkko P, Remitz A et al. Cyclosporine in the treatment of palmoplantar pustulosis. Arch Dermatol . 1993; 129:1273-9. [PubMed 8215491]

258. Baughman RD. Psoriasis and cigarettes: another nail in the coffin. Arch Dermatol . 1993; 129:1329-30. [PubMed 8215501]

259. Reitamo S, Puska P, Lassus A. Cyclosporin in the treatment of palmo-plantar pustulosis. Br J Dermatol . 1989; 120:857. [PubMed 2667617]

260. Wiesner RH, Ludwig J, Lindor KD et al. Cyclosporine in primary biliary cirrhosis. N Engl J Med . 1990; 323:1352.

261. Häyry P, von Willebrand E. Use of fine needle aspiration biopsy in differential diagnosis between nephrotoxicity and rejection. Contr Nephrol . 1986; 51:147-51.

262. Kim EE, Pjura G, Lowry P et al. Cyclosporin-A nephrotoxicity and acute cellular rejection in renal transplant recipients: correlation between radionuclide and histologic findings. Radiology . 1986; 159:443-6. [PubMed 3515421]

263. Mihatsch MJ, Steiner K, Abeywickrama KH et al. Risk factors for the development of chronic cyclosporine-nephrotoxicity. Clinical Nephrology . 1988; 29:165-75. [PubMed 3284669]

264. Parvin SD, Rees Y, Veitch PS et al. Objective measurement by ultrasound to distinguish cyclosporin A toxicity from rejection. Br J Surg . 1986; 73:1009-11. [PubMed 3539254]

265. Salaman JR, Ross WB, Griffin PJA e tal. Intrarenal pressure and renal transplant survival. Clin Transplantation . 1988; 2:228-30.

266. te Strake L, Kool LJS, Paul LC et al. Magnetic resonance imaging of renal transplants: its value in the differentiation of acute rejection and cyclosporin A nephrotoxicity. Clinical Radiology . 1988; 39:220-8. [PubMed 3293883]

267. von Willebrand E, Häyry. Cyclosporin-A deposits in renal allografts. Lancet . 1983; 2:189-92. [PubMed 6135029]

268. Winkelmann M, Bürrig KF, Koldovsky U et al. Cyclosporin A: altered renal tubular cells in urinary cytology. Lancet . 1985; 2: 667. [PubMed 2863653]

269. Taube DH, Williams DG, Hartley B et al. Differentiation between allograft rejection and cyclosporin nephrotoxicity in renal-transplant recipients. Lancet . 1985: 2:171-4.

270. Burke JF Jr, Pirsh JD, Ramos EL et al. Long-term efficacy and safety of cyclosporine in renal-transplant recipients. N Engl J Med . 1994; 331:358-63. [PubMed 8028616]

271. Luke RG. New issues in therapy after renal transplantation. N Engl J Med . 1994; 331:393-4. [PubMed 8028621]

272. Singh AK. Efficacy and safety of cyclosporine in renal-transplant recipients. N Engl J Med . 1994; 331:1777. [PubMed 7984210]

273. Bennett WM. Efficacy and safety of cyclosporine in renal-transplant recipients. N Engl J Med . 1994; 331:1777. [PubMed 7984209]

274. Burke JF Jr, Pirsch JD, Salomon DR. Efficacy and safety of cyclosporine in renal- transplant recipients. N Engl J Med . 1994; 331:1777-8.

275. Holt DW, Marsden JT, Johnston A et al. Blood cyclosporin concentrations and renal allograft dysfunction. BMJ . 1986; 293:1057-9. [PubMed 3094774]

276. Irschik E, Tilg H, Niederwieser D et al. Cyclosporin blood levels do correlate with clinical complications. Lancet . 1984; 2: ? Letter. [PubMed 6147710]

277. Lindholm A, Dahlqvist R, Groth GG et al. A prospective study of cyclosporine concentration in relation to its therapeutic effect and toxicity after renal transplantation. Br J Clin Phrmacol . 1990; 30:443-52.

278. Moyer TP, Post GR, Sterioff S et al. Cyclosporine nephrotoxicity is minimized by adjusting dosage on the basis of drug concentration in blood. Mayo Clin Proc . 1988; 63:241-7. [PubMed 3278174]

279. Lindholm A, Kahan BD. Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther . 1993; 54:205-18. [PubMed 8354028]

280. Schroeder TJ, Sridhar N, Pesce AJ et al. Clinical correlations of cyclosporine-specific and -nonspecific assays in stable renal transplants, acute rejection, and cyclosporine nephrotoxicity. Ther Drug Monit . 1993; 15:190-4. [PubMed 8332997]

281. Canafax DM. Minimizing cyclosporine concentration variability to optimize transplant outcome. Clin Transplantation . 1995; 9:1-13.

282. Lindholm A. Therapeutic monitoring of cyclosporin: an update. Eur J Clin Pharmacol . 1991; 41:273-83. [PubMed 1804639]

283. Bishop GA, Waugh J, Horvath JS et al. Diagnosis of renal allograft rejection by analysis of fine-needle aspiration biopsy specimens with immunostains and simple cytology. Lancet . 1986; 2:645-50. [PubMed 2876134]

284. Cortesini R, Stella F, Molajoni ER et al. Urinary exfoliative cytology in kidney allografts under cyclosporine therapy. Transplantation Proceedings . 1984; 16:1200-1. [PubMed 6385377]

285. Desir G, Lange R, Smith E et al. Differentiation of acute rejection from cyclosporine nephrotoxicity and acute tubular necrosis by indium-111 labelled platelet scintigraphy. Clinical Research . 1985; 33:481A.

286. Hricak H, Terrier F, Demas BE. Renal allografts: evaluation by MR imaging. Radiology . 1986; 159:435-41. [PubMed 3515420]

287. Jurewicz WA, Dykes JGA, Gunson BK et al. Indium-111-labeled platelets as a diagnostic aid in posttransplant monitoring of renal allografts in humans. Transplantation Proceedings . 1984; 16:1481-3. [PubMed 6390850]

288. Kahan BD. Clinical summation: an algorithm for the management of patients with cyclosporine-induced renal dysfunction. Transplantation Proceedings . 1985; 17(Suppl 1):303-8. [PubMed 3895669]

289. Klintmalm G, Ringdén O, Groth CG. Clinical and laboratory signs in nephrotoxicity and rejection in cyclosporine-treated renal allograft recipients. Transplantation Proceedings . 1983; 15(Suppl 1): 2815-20.

290. Matas AJ, Tellis VA, Quinn T et al. Definition, diagnosis, and management of rejection in the second to sixth months posttransplant: an overview. Trnasplantation Proceedings . 1986; 18(Suppl 1): 141-7.

291. Oh C-S, Stratta RJ, Pirsch JD et al. A simple and reliable way of differentiating acute rejection from cyclosporine nephrotoxicity in renal transplantation. Transplantation . 46:311-2.

292. Pjura GA, Kim EE, Lowry PA et al. Radionuclide differentiation of acute cellular rejection from ciclosporin nephrotoxicity. Contr Nephrol . 1987; 56:163-7.

293. Salaman JR, Griffin PJA. Fine needle intrarenal manometry in the management of renal transplant patients receiving cyclosporine. Transplantation Proceedings . 1985; 17:1275-6.

294. Sibley RK, Rynasiewicz J, Ferguson RM et al. Morphology of cyclosporine nephrotoxicity and acute rejection in patients immunosuppressed with cyclosporine and prednisone. Surgery . 1983; 94:225-34. [PubMed 6348988]

295. Sibley RK, Ferguson RM, Sutherland DER et al. Morphology of cyclosporine nephrotoxicity -prednisone immunosuppressed renal allograft recipients. Transplantation Proceedings . 1983; 15(Suppl 1):2836-41.

296. Solez K, McGraw DJ, Beschorner WE et al. Reflections on use of the renal biopsy as the “gold standard” in distinguishing transplant rejection from cyclosporine nephrotoxicity. Transplantation Proceedings . 1985; 17(Suppl 1): 123-33. [PubMed 3927535]

297. Taube D, Neild G, Hobby P et al. A comparison of the clinical, histopathologic, cytologic, and biochemical features of renal transplant rejection, cyclosporine A nephrotoxicity , and stable renal function. Transplantation Proceedings . 1985; 17(Suppl 1): 179-84. [PubMed 3895658]

298. Ubhi CS, Guillou PJ, Davison AM et al. Combination fine-needle aspiration cytology and intrarenal manometry at the onset of renal dysfunction. Br J Surg . 1987; 74:297-300. [PubMed 3555693]

299. Wagner E, Pichlmayr R, Wonigeit K et al. Differentiation between rejection and cyclosporin-A nephrotoxicity by monitoring interstitial pressure in human renal allografts. Transplantation Proceedings . 1983; 15:489-92.

300. Wijeyesinghe ECR, Hawkins T, Keavey P et al. Techmetium-99m tin colloid: its value in the diagnosis of renal transplant rejection and its potential for differentiating cyclosporin nephrotoxicity. Kidney International . 1985; 27:351.

301. Wilson RG, Shenton BK, Taylor RMR et al. Aspirate cellularity as a rapid indicator of renal allograft rejection. Br J Surgery . 1986; 73:116-7.

302. Keown PA, Stiller CR, Wallace AC. Effect of cyclosporine on the kidney. J Pediatr . 1987; 111:1029-33. [PubMed 3316576]

303. Cyclosporine interactions. In: Tatro DS, Olin BR, Hebel SK, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1995:229a,230a,233,237,238,238a,238b,238d,240,240a,242,278a,479b.

304. Norman DJ, Illingworth DR, Munson J et al. Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin. N Engl J Med . 1988; 318:46-7. [PubMed 3275891]

305. East C, Alivizatos PA, Grundy SM et al. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation. N Engl J Med . 1988; 318:47-8. [PubMed 3275892]

306. Tobert JA. Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation. N Engl J Med . 1988; 318:48. [PubMed 3257291]

307. Corpier CL, Jones PH, Suki WN et al. Rhabdomyolysis and renal injury with lovastatin use. JAMA . 1988; 260:239-41. [PubMed 3290520]

308. Cyclosporine interactions. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:201,244-5,335-6,391,393-4,411,463-4,499,541-2,569-71,575,578,854.

309. Schofield OMV, Camp RDR, Levene GM. Cyclosporin A in psoriasis: interaction with carbamazepine. Br J Dermatol . 1990; 122: 425. [PubMed 2322504]

310. Dorian P, Strauss M, Cardella C et al. Digoxin-cyclosporine interaction: severe digitalis toxicity after cyclosporine treatment. Clin Invest Med . 1988; 11:108-12. [PubMed 3396255]

311. Robieux I, Dorian P, Klein J et al. The effects of cardiac transplantation and cyclosporine therapy on digoxin pharmacokinetics. J Clin Pharmacol . 1992; 32:338-43. [PubMed 1569236]

312. Sands M, Brown RB. Interactions of cyclosporine with antimicrobial agents. Rev Infect Dis . 1989; 11:691-7. [PubMed 2682943]

313. Morgenstern GR, Powles R, Robinson B et al. Cyclosporin interaction with ketoconazole and melphalan. Lancet . 1982; 2:1342. [PubMed 6128626]

314. Zylber-Katz E, Rubinger D, Berlatzky Y. Cyclosporine interactions with metronidazole and cimtidine. Drug Intell Clin Pharm . 1988; 22:504-5. [PubMed 3293960]

315. Sugar AM, Saunders C, Idelson BA et al. Interaction of fluconazole and cyclosporine. Ann Intern Med . 1989; 110:844. [PubMed 2540690]

316. Collignon P, Hurley B, Mitchell D. Interaction of fluconazole with cyclosporin. Lancet . 1989; 1:1262. [PubMed 2566800]

317. Ehninger G, Jaschonek K, Schuler U et al. Interaction of fluconazole with cyclosporin. Lancet . 1989; 2:104-5. [PubMed 2567846]

318. Collignon P, Hurley B. Interaction between fluconazole and cyclosporin. Lancet . 1989; 2:867-8. [PubMed 2571795]

319. López-Gil JA. Fluconazole-cyclosporine interaction: a dose-dependent effect? Ann Pharmacother . 1993; 27: 427-30.

320. Back DJ, Tjia JF. Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes. Br J Clin Pharmacol . 1991; 32:624-6. [PubMed 1659439]

321. Kwan JTC, Foxall PJD, Davidson DGC et al. Interaction of cyclosporin and itraconazole. Lancet . 1987; 2:282.

322. Nováková I, Donnelly P, de Witte T et al. Itraconazole and cyclosporin nephrotoxicity. Lancet . 1987; 2:920-1. [PubMed 2889119]

323. Trenk D, Brett W, Jähnchen E et al. Time course of cyclosporin/itraconazole interaction. Lancet . 1987; 2:1335-6.

324. Kramer MR, Marshall SE, Denning DW et al. Cyclosporine and itraconazole interaction in heart and lung transplant recipients. Ann Intern Med . 1990; 113:327-9. [PubMed 2165371]

325. Lindholm A, Henricsson S. Verapamil inhibits cyclosporin metabolism. Lancet . 1987; 1:1262-3. [PubMed 2884392]

326. Maggio TG, Bartels DW. Increased cyclosporine blood concentrations due to verapamil administration. Drug Intell Clin Pharm . 1988; 22:705-7. [PubMed 3063481]

327. Robson RA, Fraenkel M, Barratt LJ et al. Cyclosporin-verapamil interaction. Br J Clin Pharmacol . 1988; 25:402-3. [PubMed 3282534]

328. Sabaté I, Grinó J, Castelao AM et al. Evaluation of cyclosporin-verapamil interaction, with observations on parent cyclosporin and metabolites. Clin Chem . 1988; 34:2151. [PubMed 3168235]

329. Tortorice KL, Heim-Duthoy KL, Awni WM et al. The effects of calcium channel blockers on cyclosporine and its metabolites in renal transplant recipients. Ther Drug Monit . 1990; 12:321-8. [PubMed 2396304]

330. Bourbigot B, Guiserix J, AiriauJ et al. Nicardipine increases cyclosporin blood levels. Lancet . 1986; 1:1447.

331. Todd P, Garioch JJ, Rademaker M et al. Nicardipine interacts with cyclosporin. Br J Dermatol . 1989; 121:820. [PubMed 2611131]

332. Kessler M, Netter P, Renoult E et al. Influence of nicardipine on renal function and plasma cyclosporin in renal transplant patients. Eur J Clin Pharmacol . 1989; 36:637-8. [PubMed 2673796]

333. Sandoz Pharmaceuticals Corporation. Practical guide: Sandimmune^® (cyclosporine). East Hanover, NJ; 1992 Jul.

334. Ross WB, Roberts D, Griffin PJA et al. Cyclosporin interaction with danazol and norethisterone. Lancet . 1986; 1:330.

335. Interactions

336. Rossi SJ, Schroeder TJ, Hariharan S et al. Prevention and management of the adverse effects associated with immunosuppressive therapy. Drug Safety . 1993; 9:104-31. [PubMed 8397889]

337. Beaufils H, de Groc F, Gubler MC et al. Hemolytic uremic syndrome in patients with Behcet's disease treated with cyclosporin A: report of 2 cases. Clinical Nephrology ?

338. Katznelson S, Wilkinson A, Rosenthal TR et al. Cyclosporine-induced hemolytic uremic syndrome: factors that obscure its diagnosis. Transplantation Proceedings . 1994; 26:2608-9. [PubMed 7940812]

339. Shulman H, Striker G, Deeg HJ et al. Nephrotoxicity of cyclosporin A after allogeneic marrow transplantation: glomerular thromboses and tubular injury. N Engl J Med . 1981; 305:1392-5. [PubMed 7029278]

340. Sommer BG, Innes JT, Whitehurst RM et al. Cyclosporine-associated renal arteriopathy reulting in loss of allograft function. Am J Surg . 1985; 149:756-64. [PubMed 3893178]

341. Nicholls S, Domizio P, Williams CB et al. Cyclosporin as initial treatment for Crohn's disease. Arch Dis Child . 1994; 71:243-7. [PubMed 7979499]

342. Camp RDR, Reitamo S, Friedmann PS et al. Cyclosporin A in severe, therapy- resistant atopic dermatitis: report of an international workshop, April 1993. Br J Dermatol . 1993; 129: 217-20. [PubMed 7654593]

343. de Prost Y, Bodemer C, Teillac D. Double-blind randomized placebo-controlled trial of local cyclosporine in atopic dermatitis. Arch Dermatol . 1989; 125:570. [PubMed 2930221]

344. Granlund H, Erkko P, Sinisalo M et al. Cyclosporin in atopic dermatitis: time to relapse and effect of intermittent therapy. Br J Dermatol . 1995: 132:106-12.

345. Munro CS, Higgins EM, Marks JM et al. Cyclosporin A in atopic dermatitis: therapeutic response is dissociated from effects on allergic reactions. Br J Dermatol . 1991: 124:43-8.

346. Ross JS, Camp RDR. Cyclosporin A in atopic dermatitis. Br J Dermatol . 1990; 122(Suppl 36):41-5. [PubMed 2196083]

347. Salek MS, Finlay AY, Luscombe DK et al. Cyclosporin greatly improves the quality of life of adults with severe atopic dermatitis. a randomized, double-blind, placebo-controlled trial. Br J Dermatol . 1993; 129:422-30. [PubMed 8217757]

348. Sepp N, Fritsch PO. Can cyclosporin A induce permanent remission of atopic dermatitis? Br J Dermatol . 1993; 128:213-6.

349. Sowden JM, Berth-Jones J, Ross JS et al. Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis. Lancet . 1991; 338:137- 40. [PubMed 1677063]

350. van Joost T, Stolz E, Heule F. Efficacy of low-dose cyclosporine in severe atopic skin disease. Arch Dermatol . 1987; 123:166-7. [PubMed 3813588]

351. van Joost T, Heule F, Korstanje M et al. Cyclosporin in atopic dermatitis: a multicentre placebo-controlled study. Br J Dermatol . 1994: 130:634-40.

352. Lapidoth M, David M, Ben-Amitai D et al. The efficacy of combined treatment with prednisone and cyclosporine in patients with pemphigus: preliminary study. J Am Acad Dermatol . 1994; 30:752-7. [PubMed 8176015]

353. Luisi AF, Stoukides CA. Cyclosporine for the treatment of pemphigus vulgaris. Ann Pharmacother . 1994; 28:1183-5. [PubMed 7841576]

354. Thivolet J, Barthelemy H, Rigot-Muller G et al. Effects of cyclosporin on bullous pemphigoid and pemphigus. Lancet . 1985; 1:334-5. [PubMed 2857378]

355. Gupta AK, Ellis CN, Nickoloff BJ et al. Oral cyclosporine in the treatment of inflammatory and noninflammatory dermatoses. Arch Dermatol . 1990; 126:339-50. [PubMed 2178558]

356. Balato N, De Rosa S, Bordone F et al. Dermatological application of cyclosporine. Arch Dermatol . 1989; 125:1430-1. [PubMed 2535658]

357. Borrego L, Ruiz-Rodriguez R, de Frutos JO et al. Vulvar lichen planus treated with tropical cyclosporine. Arch Dermatol . 1993; 129:794.

358. Eisen D, Griffiths CEM, Ellis CN et al. Cyclosporin wash for oral lichen planus. Lancet . 1990; 335:535-6. [PubMed 1689788]

359. Eisen D, Ellis CN, Duell EA et al. Effect of topical cyclosporine rinse on oral lichen planus: a double-blind analysis. N Engl J Med . 1990; 323:290-4. [PubMed 2195345]

360. Ho VC, Conklin RJ. Effect of topical cyclosporine rinse on oral lichen planus. N Engl J Med . 325:435. Letter.

361. Eisen D, Voorhees JJ. Effect of topical cyclosporine rinse on oral lichen planus. N Engl J Med . 325:435. Letter.

362. Higgins EM, Munro CS, Friedmann PS et al. Cyclosporin A in the treatment of lichen planus. Arch Dermatol . 1989; 125:1436. [PubMed 2802654]

363. Levell NJ, MacLeod RI, Marks JM. Lack of effect of cyclosporin mouthwash in oral lichen planus. Lancet . 1991; 337:796-7. [PubMed 1672422]

364. Levell NJ, Munro CS, Marks JM. Severe lichen planus clears with very low-dose cyclosporin. Br J Dermatol . 1992; 127:66-7. [PubMed 1637703]

365. Pigatto PD, Chiappino G, Bigardi A et al. Cyclosporin A for treatment of severe lichen planus. Br J Dermatol . 1990; 122:121-3. [PubMed 2297500]

366. Porter SR, Scully C, Eveson JW. The efficacy of topical cyclosporin in the managmenet of desquamative gingivitis due to lichen planus. Br J Dermatol . 1993; 129:753-5. [PubMed 8286271]

367. Dougados M, Awada H, Amor B. Cyclosporin in rheumatoid arthritis: a double blind, placebo controlled study in 52 patients. Annals of the Rheumatic Diseases . 1988; 47:127- 33. [PubMed 3281603]

368. Forre O, Bjerkhoel F, Salvesen CF et al. An open, controlled, randomized comparison of cyclosporine and azathioprine in the treatment of rheumatoid arthritis: a preliminary report. Arthritis Rheum . 1987; 30:88-92. [PubMed 3814200]

369. Horton S, Resman-Targoff BH, Thompson DF. Use of cyclosporine in rheumatoid arthritis. Ann Pharmacother . 1993; 27:44-6. [PubMed 8431620]

370. Landewé RBM, Goei Thé HS, van Rijthoven AWAM et al. A randomized, double-blind, 24-week controlled study of low-dose cyclosporine versus chloroquine for early rheumatoid arthritis. Arthritis Rheum . 1994; 37:637-43. [PubMed 8185690]

371. Madhok R, Torley HI, Capell HA. A study of the longterm efficacy and toxicity of cyclosporine A in rheumatoid arthritis. J Rheumatol . 1991; 18: 1485-9.

372. Sigidin YA, Usova SB. Comparative study of cyclosporin A in systemic rheumatoid arthritis. Int J Immunotherapy . 1994; 10:61-5.

373. Tugwell P, Bennett KJ, Chalmers A et al. Low-doe cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet . 1990; 335:1051-5. [PubMed 1970370]

374. van Rijthoven AWAM, Dijkmans BAC, Goei The HS et al. Cyclosporin treatment for rheumatoid arthritis: a placebo controlled, double blind, multicentre study. Annals of the Rheumatic Diseases . 1986; 45:726-31. [PubMed 3532966]

375. Weinblatt ME, Coblyn JS, Fraser PA et al. Cyclosporin A treatment of refractory rheumatoid arthritis. Arthritis Rheum . 1987; 30:11-7. [PubMed 3814192]

376. Yocum DE, Klippel JH, Wilder RL et al. Cyclosporin A in severe, treatment- refractory rheumatoid arthritis: a rnadomized study. Ann Intern Med . 1988; 109:863-9. [PubMed 3190040]

377. Bennett WM. The nephrotoxicity of immunosuppressive drugs. Clinical Nephrology . 1995; 43(Suppl 1):S3-7. [PubMed 7540121]

378. Wadhwa NK, Schroeder TJ, Pesce AJ et al. Cyclosporine drug interactions: a review. Therapeutic Drug Monitoring . 1987; 9:399-406. [PubMed 3321582]

379. Yee GC, McGuire TR. Pharmacokinetic drug interactions with cyclosporin (Part I). Clin Pharmacokinet . 1990; 19:319-32. [PubMed 2208899]

380. Yee GC, McGuire TR. Pharmacokinetic drug interactions with cyclosporin (Part II). Clin Pharmacokinet . 1990; 19:400-15. [PubMed 2268987]

381. Brown AL, Wilkinson R, Thomas TH et al. The effect of short-term low-dose cyclosporin on renal function and blood pressure in patients with psoriasis. Br J Dermatol . 1993; 128:550-5. [PubMed 8504048]

382. Edwards BD, Chalmers RJG, O'Driscoll JB et al. Angiotensin II as a risk factor for cyclosporin nephrotoxicity in patients with psoriasis. 1994; 41:350-6.

383. Feutren G, Friend D, Timonen P et al. Predictive value of cyclosporin A level for efficacy or renal dysfunction in psoriasis. Br J Dermatol . 1990; 122(Suppl 36):85-93. [PubMed 2369572]

384. Feutren G, Abeywickrama K, Friend D et al. Renal function and blood pressure in psoriatic patients treated with cyclosporin A. Br J Dermatol . 1990; 122(Suppl 36):57-69. [PubMed 2196085]

385. Gupta AK, Rocher LL, Schmaltz SP et al. Short-term changes in renal function, blood presure, and electrolyte levels in patients receiving cyclosporine for dermatologic disorders. Arch Intern Med . 1991; 151:356-62. [PubMed 1992963]

386. Korstanje MJ, Bilo HJG, Stoof TJ. Sustained renal function loss in psoriasis patients after withdrawal of low-dose cyclosporin therapy. Br J Dermatol . 1992; 127:501-4. [PubMed 1467290]

387. Pei Y, Scholey JW, Katz A et al. Chronic nephrotoxicity in psoriatic patients treated with low-dose cyclosporine. American Journal of Kidney Diseases . 1994; 23:528-36. [PubMed 8154488]

388. Powles AV, Carmichael D, Hulme B et al. Renal function after long-term low-dose cyclosporin for psoriasis. Br J Dermatol . 1990; 122:665-9. [PubMed 2112945]

389. Powles AV, Cook T, Hulme B et al. Renal function and biopsy findings after 5 years' treatment with low-dose cyclosporin for psoriasis. Br J Dermatol . 1993; 128:159-65. [PubMed 8457449]

390. International Kidney Biopsy Registry of Cyclosporin A (Sandimmun®) in Autoimmune Diseases. Kidney biopsies in control or cyclosporin A-treated psoriatic patients. Br J Dermatol . 1990; 122(Suppl 36):95-100. [PubMed 2369573]

391. Sandoz Pharmaceuticals Corporation. Neoral^® (cyclosporine for microemulsion) soft gelatin capsules and oral solution prescribing information. East Hanover, NJ; 1995 June.

392. Scott JP, Higenbottam TW. Adverse reactions and interactions of cyclosporin. Medical Toxicology . 1988; 3:107-27. [PubMed 3287088]

393. Tugwell P, Pincus T, Yocum D et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med . 1995; 333:137-41. [PubMed 7791814]

394. Breedveld FC. New perspectives on treating rheumatoid arthritis. N Engl J Med . 1995; 333:183-4. [PubMed 7791822]

395. Bernstein CN, Shanahan F. Cyclosporine and inflammatory bowel disease: still more questions. Gastroenterology . 1995; 108:943-5. [PubMed 7875503]

396. Feagan BG. Reply. Gastroenterology . 1995; 108:945. [PubMed 7875504]

397. Stange EF, Modigliani R, Pena AS et al. European trial of cyclosporine in chronic active Crohn's disease: a 12-month study. Gastroentrology . 1995; 109:774-82.

398. Sandborn WJ. Cyclosporine therapy for inflammatory bowel disease: definitive answers and remaining questions. Gastroenterology . 1995; 109:1001-3. [PubMed 7657085]

399. Cooney GF, Mochon M, Kaiser B et al. Effects of carbamazepine on cyclosporine metabolism in pediatric renal transplant recipients. Pharmacotherapy . 1995; 15:353-6. [PubMed 7667170]

400. Ferrari SL, Goffin E, Mourad M et al. The interaction between clarithromycin and cyclosporine in kidney transplant recipients. Trnasplantation . 1994; 58:725-7.

401. Slavin J, Taylor J. Cyclosporin, nifedipine, and gingival hyperplasia. Lancet . 1987; II:739.

402. Gersema LM, Porter CB, Russell EH. Suspected drug interaction between cyclosporine and clarithromycin. Journal of Heart and Lung Transplantation . 1994; 13:343-5. [PubMed 8031821]

403. Gorrie M, Beaman M, Nicholls A et al. Allopurinol interaction with cyclosporin. BMJ . 1994; 308:113. [PubMed 8298381]

404. Stevens SL, Goldman MH. Cyclosporine toxicity associated with allopurinol. South Med J . 1992; 85:1265-6. [PubMed 1470981]

405. Ellis CN, Fradin MS, Hamilton TA et al. Duration of remission during maintenance cyclosporine therapy for psoriasis: relationship to maintenance dose and degree of improvement during initial therapy. Arch Dermatol . 1995; 131:791-5. [PubMed 7611794]

406. Koo J. Cyclosporine in dermatology: fears and opportunities. Arch Dermatol . 1995; 131:842-5. [PubMed 7611807]

407. Kovarik JM, Mueller EA, Johnston A et al. Bioequivalence of soft gelatin capsules and oral solution of a new cyclosporine formulation. Pharmacotherapy . 1993; 13:613-7. [PubMed 8302687]

408. Awni WM, Kasiske BL, Heim-Duthoy K et al. Long-term cyclosporine pharmacokinetic changes in renal transplant recipients: effects of binding and metabolism. Clin Pharmacol Ther . 1989; 45: 41-8. [PubMed 2642778]

409. Kovarik JM, Vernillet L, Mueller EA et al. Cyclosporine disposition and metabolite profiles in renal transplant patients receiving a microemusion formulation. Ther Drug Monitoring . 1994; 16:519-25.

410. Trull AK, Tan KKC, Tan L et al. Absorption of cyclosporin from conventional and new microemulsion oral formulations in liver trnasplant recipients with external biliary diversion. Br J Clin Pharmacol . 1995; 39:627-31. [PubMed 7654480]

411. Trull AK, Tan KKC, Uttridge J et al. Cyclosporin absorption from microemulsion formulation in liver transplant recipient. Lancet . 1993; 341:433. [PubMed 8094190]

412. Sketris IS, McAlister V, Wright MR. Increased cyclosporine bioavailability from a microemulsion formulation in a liver transplant recipient. Ann Pharmacother . 1994; 28:962. [PubMed 7949523]

413. Van den Borne BEEM, Landewé RBM, Goei The HS et al. Relative bioavailability of a new oral form of cyclosporin A in patients with rheumatoid arthritis. BR J Clin Pharmacol . 1995; 39:172-5. [PubMed 7742156]

414. Holt DW, Mueller EA, Kovarik JM et al. Sandimmun Neoral pharmacokinetics: impact of the new oral formulation. Transplantation Proceedings . 1995; 27:1434-7. [PubMed 7878935]

415. Mikhail G, Eadon H, Leaver N et al. Use of Neoral in heart transplant recipients. Transplantation Proceedingsd . 1994; 26:2985-7.

416. Mueller EA, Kovark JM, van Bree JB et al. Influence of a fat-rich meal on the pharmacokinetics of a new oral formulation of cyclosporine in a crossover comparison with the market formulation. Pharmaceutical Research . 1994; 11:151-5. [PubMed 8140046]

417. Kahan BD, Dunn J, Fitts C et al. Reduced inter- and intrasubject variability in cyclosporine pharmacokinetics in renal transplant recipients treated with a microemulsion formulation in conjunction with fasting, low-fat meals, or high-fat meals. Transplantation . 1995; 59:505-11. [PubMed 7878754]

418. Kovarik JM, Mueller EA, van Bree JB et al. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a micoemulsion formulation. Journal of Pharmaceutical Sciences . 1994; 83:444-6. [PubMed 8207699]

419. Kovarik JM, Mueller EA, van Bree JB et al. Cyclosporine pharmacokinetics and variability from a microemulsion formulation: a multicenter investigation in kidney transplant patients. Transplantation . 1994; 58:658-63. [PubMed 7940685]

420. Sketris IS, Gulanikar AC, Methot ME. Cyclosporine-nonsteroidal anti-inflammatory drugs: potential for additive renal dysfunction. Canadian Journal of Hospital Pharmacy . 1992; 45:117-8.

421. Branthwaite JP, Nicholls A. Cyclosporin and diclofenac interaction in rheumatoid arthritis. Lancet . 1991; 337:252. [PubMed 1670893]

422. Mueller EA, Kovarik JM, van Bree JB et al. Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation. Pharmaceutical Research . 1994; 11:301-4. [PubMed 8165192]

423. Friman S, Bäckman L. A new microemulsion formulation of cyclopsorin: pharmacokinetic and clinical features. Clin Pharmacokinet . 1996; 30:181-93. [PubMed 8882300]

424. Holt DW, Johnston A, Roberts NB et al. Methodological and clinical aspects of cyclosporin monitoring: report of the Association of Clinical Biochemists task force. Ann Clin Biochem . 1994; 31:420-46. [PubMed 7832569]

425. Lindholm A. Factors influencing the pharmacokinetics of cyclosproine in man. Ther Drug Monitor . 1991; 13:465-77.

426. Yee GC, Mills G, Shaffer R et al. Renal cyclosporine clearance in marrow transplant recipients: age-related variation. J Clin Pharmacol . 1986; 26:658-61. [PubMed 3540031]

427. Ptachcinski RJ, Burckart GJ, Rosenthal JT et al. Cyclosporine pharmacokinetics in children following cadaveric renal transplantation. Transplant Proc . 1986; 18:766-7.

428. Yee GC, Lennon TP, Gmur DJ et al. Age-dependent cyclosporine: pharmacokinetics in marrow transplant recipients. Clin Pharmacol Ther . 1986; 40:438-43. [PubMed 3530588]

429. Roche. Posicor^® (mibefradil hydrochloride) tablets prescribing information. Nutley, NJ; 1997 Dec.

430. Ellison RH. Dear doctor letter regarding appropriate use of Posicor^®. Nutley, NJ: Roche Laboratories; 1997 Dec.

431. Sandoz. Neoral^® (cyclosporine for microemulsion) soft gelatin capsules and oral solution prescribing information. East Hanover, NJ; 1997 Jun.

432. Yee GC, Stanley DL, Pessa LJ et al. Effect of grapefruit juice on blood cyclosporin concentration. Lancet . 1995; 345:955-6. [PubMed 7715295]

433. Hollander AAMJ, van Rooij J, Lentjes EGWM et al. The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clin Pharmacol Ther . 1995; 57:318-24. [PubMed 7697949]

434. Bailey DG, Arnold JMO, Spence JD. Grapefruit juice and drugs: how significant is the interaction? Clin Pharmacokinet . 1994; 26:91-8.

435. Cyclosporine/food (grapefruit juice). In: Tatro DS, Olin BR, Hebel SK eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1996(July):233b.

436. Midazolam (Versed) interactions: grapefruit juice. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1996:932.

437. Merkel U, Sigusch H, Hoffmann A. Grapefruit juice inhibits 7-hydroxylation of coumarin in healthy volunteers. Eur J Clin Pharmacol . 1994; 46:175-7. [PubMed 8039540]

438. Proppe DG, Hoch OD, McLean AJ et al. Influence of chronic ingestion of grapefruit juice on steady-state blood concentrations of cyclosporine A in renal transplant patients with stable graft function. Br J Clin Pharmacol . 1995; 39:337-8. [PubMed 7619679]

439. Soons PA, Vogels BAPM, Roosemalen MCM et al. Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans. Clin Pharmacol Ther . 1991; 50:394-403. [PubMed 1914375]

440. Fuhr U, Klittich K, Staib AH. Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man. Br J Clin Pharmacol . 1993; 35:431-6. [PubMed 8485024]

441. Bailey DG, Spence JD, Munoz C et al. Interaction of citrus juices with felodipine and nifedipine. Lancet . 1991; 337:268-9. [PubMed 1671113]

442. Campana C, Regazzi MB, Buggia I et al. Clinically significant drug interactions with cyclosporin: an update. Clin Pharmacokinet . 1996; 30:141-179. [PubMed 8906896]

443. Kupferschmidt HHT, Ha HR, Ziegler WH et al. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther . 1995; 58:20-8. [PubMed 7628179]

444. Sandoz Pharmaceuticals Corp. Neoral (cyclosporine for microemulsion) soft gelatin capsules and oral solution prescribing information. East Hanover, NJ; 1995 Sep.

445. Johnston A, Holt DW. Effect of grapefruit juice on blood cyclosporin concentration. Lancet . 1995; 346:122-3. [PubMed 7603196]

446. Hollander AAMJ, van der Woude FJ, Cohen AF. Effect of grapefruit juice on blood cyclosporin concentration. Lancet . 1995; 346:123. [PubMed 7677856]

447. Yee GC, Lowenthal DT. Effect of grapefruit juice on blood cyclosporin concentration. Lancet . 1995; 346:123-4. [PubMed 7677856]

448. Ameer B, Weintraub RA, Johnson JV et al. Flavanone absorption after naringin, hesperidin, and citrus administration. Clin Pharmacol Ther . 1996; 60:34-40. [PubMed 8689809]

449. Edwards DJ, BellevueFH, Woster PM. Identification of 6',7'-dihydroxybergamottin, a cytochrome P-450 inhibitor in grapefruit juice. Drug Metabol Dispos . (in press)

450. Edwards DJ, Bernier SM. Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice. Life Sci . 1996; 59:1025-30. [PubMed 8809221]

451. Lundahl J, Regardh CG, Edgar B et al. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects. Eur J Clin Pharmacol . 1995; 49:61-7. [PubMed 8751023]

452. Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clin Pharmacokinet . 1997; 33:103-21. [PubMed 9260034]

453. Ducharme MP, Warbasse LH, Edwards DJ. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther . 1995; 57:485-91. [PubMed 7768070]

454. Hukkinen SK, Varhe A, Olkkola KT et al. Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice. Clin Pharmacol Ther . 1995; 58:127-31. [PubMed 7648762]

455. Anon. Grapefruit juice interactions with drugs. Med Lett Drugs Ther . 1995; 37:73-4. [PubMed 7630329]

456. Zachariae H, Kragballe K, Hansen HE et al. Renal biopsy findings in long-term cyclosporin treatment of psoriasis. Br J Dermatol . 1997; 136:531-5. [PubMed 9155953]

457. Edwards BD, Bhatnagar D, Mackness MI et al. Effect of low-dose cyclosporin on plasma lipoproteins and markers of cholestasis in patients with psoriasis. Q J Med . 1995; 88:109-13.

458. Berth-Jones J, Voorhees JJ. Consensus conference on cyclosporin A microemulsion for psoriasis, June 1996. Br J Dermatol . 1996; 135:775-7. [PubMed 8977680]

459. Grossman RM, Maugee E, Dubertret L. Cervical intraepithelial neoplasia in a patient receiving long-term cyclosporin for the treatment of severe plaque psoriasis. Br J Dermatol . 1996; 135:147-8. [PubMed 8776385]

460. Altman RD, Perez GO, Sfakianakis GN. Interaction of cyclosporine A and nonsteroidal anti-inflammatory drugs on renal function in patients with rheumatoid arthritis. Am J Med . 1992; 93:396-402. [PubMed 1415303]

461. Kovarik JM, Kurki P, Mueller E et al. Diclofenac combined with cyclosporine in treatment refractory rheumatoid arthritis: longitudinal safety assessment and evidence of a pharmacokinetic/dynamic interaction. J Rheumatol . 1996; 23:2033-8. [PubMed 8970037]

462. Kovarik JM, Mueller EA, Gerbeau C et al. Cyclosporine and nonsteroidal antiinflammatory drugs: exploring potential drug interactions and their implications for the treatment of rheumatoid arthritis. J Clin Pharmacol . 1997; 37:336-43. [PubMed 9115060]

463. Lowe NJ, Wieder JM, Rosenbach A et al. Long-term low-dose cyclosporine therapy for severe psoriasis: effects on renal function and structure. J Am Acad Dermatol . 1996; 35:710-9. [PubMed 8912566]

464. Ad Hoc Committee on Clinical Guidelines, American College of Rheumatology. Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum . 1996; 39:723-31. [PubMed 8639168]

465. Tugwell P, Ludwin D, Gent M et al. Interaction between cyclosporin A and nonsteroidal antiinflammatory drugs. J Rheumtol . 1997; 24:1122-5.

466. Grossman RM, Chevret S, Abi-Rached J et al. Long-term safety of cyclosporine in the treatment of psoriasis. Arch Dermatol . 1996; 132:623-9. [PubMed 8651712]

467. Rodriguez F, Krayenbuhl JC, Harrison WB et al. Renal biopsy findings and followup of renal function in rheumatoid arthritis patients treated with cyclosporin A: an update from the International Kidney Biopsy Registry. Arthritis Rheum . 1996; 39:1491-8. [PubMed 8814060]

468. Feutren G, Mihatsch MJ. Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. N Engl J Med . 1992; 326:1654-60. [PubMed 1588978]

469. Landewe RBM, Dijkmans BAC, van der Woude FJ et al. Longterm low dose cyclosporine in patients with rheumatoid arthritis: renal function loss without stuctural nephropathy. J Rheumatol . 1996; 23:61-4. [PubMed 8838509]

470. Pei Y. Chronic cyclosporine nephrotoxicity in rheumatoid arthritis. J Rheumtol . 1996; 23:4-5.

471. Ludwin D, Alexopoulou I, Esdaile JM et al. Renal biopsy specimens from patients with rheumatoid arthritis and apparently normal renal function after therapy with cyclosporine. Am J Kid Dis . 1994; 23:260-5. [PubMed 8311085]

472. Sund S, Forre O, Berg KJ et al. Morphological and functional renal effects of long- term low-dose cyclosporin A treatment in patients with rheumatoid arthritis. Clin Nephrol . 1994; 41:33-40. [PubMed 8137567]

473. Pasero G, Priolo F, Marubini E et al. Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum . 1996; 39:1006-15. [PubMed 8651963]

474. Shupack J, Abel E, Bauer E et al. Cyclosporine as maintenance therapy in patients with severe psoriasis. J Am Acad Dermatol . 1997; 36:423-32. [PubMed 9091474]

475. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum . 2002; 46:328-46. [PubMed 11840435]

476. Abbott Laboratories. Gengraf^® (cyclosporine) capsules, USP (modified), prescribing information. North Chicago, IL; 2009 Jun.

477. Abbott Laboratories. Gengraf^® (cyclosporine) oral solution, USP (modified), prescribing information. North Chicago, IL; 2009 Jun.

478. Novartis Pharmaceuticals Corporation. Neoral^® (cyclosporine) soft gelatin capsules, USP (modified), and oral solution, USP (modified), prescribing information. East Hanover, NJ; 2009 Mar.

479. Novartis Pharmaceuticals Corporation. Sandimmune^® (cyclosporine) soft gelatin capsules, oral solution, and injection prescribing information. East Hanover, NJ; 2008 June.

480. Food and Drug Administration. Electronic Orange Book. From FDA website. Accessed 4 Jan 2006. [Web]

481. Carnahan W, Cooper TY. Neoral-to-Gengraf conversion in renal transplant recipients. Transplant Proc . 2003; 35:1308-13. [PubMed 12826145]

482. Roza A, Tomlanovich S, Merion R et al. Conversion of stable renal allograft recipients to a bioequivalent cyclosporine formulation. Transplantation . 2002; 74:1013-7. [PubMed 12394847]

483. Abbott Laboratories, North Chicago, IL: Personal communication.

484. Hanauer SB, Sandborn W, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn's disease in adults: Practice Guidelines. Am J Gastroenterol . 2001; 96:635-43. [PubMed 11280528]

485. Scribano M, Pantera C. Review article: medical treatment of moderate to severe Crohn's disease. Aliment Pharmacol Ther . 2003; 17 (Suppl. 2):23-30. [PubMed 12786609]

486. Hanauer SB, Present DH. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord. 2003; 3:81-92. Selby WS. Current issues in Crohn's disease. Rev Gastroenetrol Disord . 2003; 3:81-92.

487. Hanauer SB. Inflammatory bowel disease. N Engl J Med . 1996; 334:841-8. [PubMed 8596552]

488. Podolsky DK. Inflammatory bowel disease. N Engl J Med . 2002; 347:417-29. [PubMed 12167685]

489. Cat H, Sophani I, Lemann M, Modiglani R et al. Cyclosporin treatment of anal and perianal lesions associated with Crohn's disease. Turk J Gastroenterol . 2003; 14: 121-7. [PubMed 14614639]

490. Haslam N, Hearing SD, Probert CS. Audit of cyclosporin use in inflammatory bowel disease: limited benefits, numerous side-effects. Eur J Gastroenterol Hepatol . 2000; 12:657-60. [PubMed 10912486]

491. Löfberg R. Review article: medical treatment of mild to moderately active Crohn's disease. Aliment Pharmacol Ther . 2003; 17 (Suppl 2):18-22.

492. Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn's disease with intravenous cyclosporine. Am J Gastroenterol . 1998; 93: 442-8. [PubMed 9517654]

493. Korelitz BI, Adler DJ, Mendelsohn RA et al. Long-term experience with 6-mercaptopurine in the treatment of Crohn's disease. Am J Gastroenterol. 1993; 88:1198-205.

494. Present DH, Korelitz BI, Wisch N et al. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med . 1980; 302: 981-7. [PubMed 6102739]

584. Food and Drug Administration. Information for healthcare professionals: immunosuppressant drugs, required labeling changes [sirolimus (marketed as Rapamune), cyclosporine (marketed as Sandimmune and generics), cyclosporine modified (marketed as Neoral and generics), mycophenolate mofetil (marketed as Cellcept and generic), mycophenolic acid (marketed as Myfortic)]. Rockville, MD; July 14, 2009. From FDA website [Web]/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm171654.htm.

585. Wiseman AC. Polyomavirus nephropathy: a current perspective and clinical considerations. Am J Kidney Dis . 2009; 54:131-42. [PubMed 19394729]

586. Bonvoisin C, Weekers L, Xhignesse P et al. Polyomavirus in renal transplantation: a hot problem. Transplantation . 2008; 85:S42-8. [PubMed 18401263]

587. Mannon RB. Polyomavirus nephropathy: what have we learned?. Transplantation . 2004; 77:1313-8. [PubMed 15167583]

588. Ziedina I, Folkmane I, Chapenko S et al. Reactivation of BK Virus in the Early Period After Kidney Transplantation. Transplant Proc . 2009; 41:766-8. [PubMed 19328975]

589. Dharnidharka VR, Cherikh WS, Abbott KC. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation . 2009; 87:1019-26. [PubMed 19352121]

590. Alméras C, Foulongne V, Garrigue V et al. Does reduction in immunosuppression in viremic patients prevent BK virus nephropathy in de novo renal transplant recipients? A prospective study. Transplantation . 2008; 85:1099-104. [PubMed 18431228]

591. Hirsch HH, Brennan DC, Drachenberg CB et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation . 2005; 79:1277-86. [PubMed 15912088]

592. Benavides CA, Pollard VB, Mauiyyedi S et al. BK virus-associated nephropathy in sirolimus-treated renal transplant patients: incidence, course, and clinical outcomes. Transplantation . 2007; 84:83-8. [PubMed 17627242]

593. Actelion Pharmaceuticals. Tracleer^® (bosentan) tablets prescribing information. South San Francisco, CA; 2009 Aug.

594. Novartis Pharmaceuticals Corporation. Neoral^® (cyclosporine) soft gelatin capsules, USP (modified), and oral solution, USP (modified), prescribing information. East Hanover, NJ; 2009 Oct.

595. Novartis Pharmaceuticals Corporation. Sandimmune^® (cyclosporine) soft gelatin capsules, oral solution, and injection prescribing information. East Hanover, NJ; 2009 Oct.

section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

cycloSPORINE

Copyright ⬆ ⬇

References ⬆