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cyclosporine modified 25 mg generic gengraf, neoral

Out of Stock Manufacturer MAYNE PHARMA IN 51862045847
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Uses

Cyclosporine is used for the prevention of rejection of kidney, liver, or heart allografts. The manufacturers and some clinicians recommend that cyclosporine be used in conjunction with corticosteroid therapy, at least initially. Cyclosporine is also used for the treatment of chronic allograft rejection in patients previously treated with other immunosuppressive agents (e.g., azathioprine).

Renal Allotransplantation

Cyclosporine is used to prolong graft survival of allogeneic renal transplants. Therapy with cyclosporine alone has achieved graft survival rates ranging from 71-91% 1 year after renal transplantation. In a retrospective study, patient and graft survival rates were 86 and 70%, respectively, 4 years after transplantation in cyclosporine-treated patients.

Concomitant administration of cyclosporine and corticosteroids in some studies has resulted in reduction of cyclosporine dosage and decreased frequency of cyclosporine's nephrotoxic effects while continuing to optimally prolong graft survival; however, some clinicians suggest that concomitant administration of cyclosporine and corticosteroids does not increase effectiveness and may increase the frequency of adverse systemic effects (e.g., lymphoma). In a study in renal allograft recipients receiving cyclosporine alone or in combination with corticosteroids, graft survival rates after 1 year were 88 vs 84%, respectively; infectious complications and hypertension occurred more frequently in patients receiving combined therapy with cyclosporine and a corticosteroid than in those receiving cyclosporine alone. Concomitant administration of cyclosporine and corticosteroids did not improve renal function and was associated with increased frequency of lymphoma, probably resulting from excessive immunosuppression. Although the manufacturers recommend that cyclosporine be used in conjunction with corticosteroid therapy, at least initially, further study is needed to determine the role of concomitant therapy in renal allograft recipients.

When immunosuppressive therapy with cyclosporine alone or combined with corticosteroids has been compared with combined azathioprine and corticosteroid therapy, graft survival rates generally were equivalent or higher in patients receiving cyclosporine with or without corticosteroids. In patients with renal allografts, the 1-year actuarial graft survival rates for cyclosporine vs combined azathioprine and corticosteroid therapy have been reported to be 72-77 vs 52-62%, respectively; the 1-year patient survival rates for cyclosporine vs combined azathioprine and corticosteroid therapy were 88-94 vs 76-92%, respectively. Some cyclosporine-treated patients also received periodic corticosteroid therapy for acute rejection episodes. The 4-year actuarial graft survival rates for these therapies have been reported to be 76 vs 62%, respectively, and the 4-year actuarial patient survival rates were 86 vs 70%, respectively. In one study, graft survival rate in cyclosporine-treated patients was higher in patients receiving first renal allografts than in those receiving second ones and in patients receiving HLA-A and/or B mismatched allografts than in those receiving allografts matched at HLA-A and B loci; there was no correlation in graft survival with warm or cold ischemia or with anti-HLA antibodies. Cyclosporine-treated patients generally have had higher serum creatinine concentrations than those receiving combined azathioprine and corticosteroid therapy. The relative effects of prophylactic immunosuppressive regimens containing cyclosporine and/or equine antithymocyte globulin (ATG) on graft survival rates remain to be determined. Results of several comparative studies indicate that the effects on graft survival rates of prophylactic immunosuppressive regimens containing cyclosporine or equine antilymphocyte globulin (ALG) are similar.

Although cyclosporine prolongs graft survival, the drug may not prevent acute episodes of renal allograft rejection. The number of patients experiencing acute episodes of renal allograft rejection and the median time to onset of these episodes (about 1 week) have been reported to be similar for cyclosporine- or combined azathioprine/corticosteroid-treated patients. However, in one study, first acute episodes of rejection were substantially less severe in patients receiving cyclosporine than in those receiving combined azathioprine and corticosteroid therapy. In some cyclosporine-treated patients, renal graft losses resulting from irreversible acute graft rejection may be associated with persistently low trough serum concentrations of the drug; however, optimum therapeutic trough concentrations have not been determined. The occurrence of graft rejection is difficult to differentiate from cyclosporine-induced nephrotoxicity.(See Cautions: Renal Effects.) Rapid increases in serum creatinine concentration that occur simultaneously with low blood or plasma cyclosporine concentrations may indicate graft rejection.

Some clinicians recommend that cyclosporine generally be discontinued and combined therapy with azathioprine and corticosteroids be initiated in patients who do not tolerate cyclosporine (e.g., nephrotoxicity) or in whom intractable rejection occurs. In one study, the 1-year actuarial graft survival rate in patients switched from cyclosporine to combined azathioprine and corticosteroid therapy was 60%. Conversion to immunosuppressive therapy with azathioprine and corticosteroids usually results in decreased serum creatinine concentrations; however, complications, including acute rejection episodes, serious infections, or azathioprine-induced leukopenia, may occur. In one study, the need to switch from cyclosporine to combined azathioprine and corticosteroid therapy because of cyclosporine-induced nephrotoxicity or intractable rejection was eliminated when routine (3 times weekly) monitoring of trough serum cyclosporine concentrations was initiated; however, optimum trough concentrations have not been determined.

Hepatic Allotransplantation

Cyclosporine is used to prolong graft and patient survival in hepatic allograft recipients. Administration of cyclosporine and low-dose prednisone has resulted in 1-year actuarial patient survival rates of 60-80% in a limited number of hepatic allograft recipients. However, response rates may be variable and may depend on the underlying condition of the patient or the immunosuppressive regimen used. Cyclosporine's effectiveness in hepatic allotransplantation has been shown in children and adults. Decreased frequency of postoperative infectious complications may be observed in hepatic allograft recipients who have received cyclosporine compared with those treated with other immunosuppressive therapy.

Cardiac Allotransplantation

Cyclosporine is used to prolong graft and patient survival in cardiac allograft recipients. The drug has been used concomitantly with low-dose corticosteroid therapy to decrease the frequency and clinical severity of rejection episodes, reduce infectious complications compared with other immunosuppressive agents, and facilitate early patient rehabilitation following cardiac transplantation. Two-year actuarial patient survival rates for cardiac allograft recipients receiving cyclosporine vs combined azathioprine and corticosteroid therapy have been reported to be 77 vs 58%, respectively, in a limited number of patients.

Cyclosporine has also been used in a limited number of patients with combined heart-lung transplantation.

Bone Marrow Allotransplantation

The value of cyclosporine in the prevention of acute graft-vs-host disease following bone marrow transplantation remains to be clearly established. Results of studies to date suggest that prophylaxis with cyclosporine is comparable to, but not more effective than, prophylaxis with methotrexate for the prevention or amelioration of acute graft-vs-host disease or improving survival in patients undergoing bone marrow transplantation for leukemias. Limited data suggest that prophylactic combination therapy with cyclosporine and methotrexate is more effective for the prevention or amelioration of acute graft-vs-host disease and possibly improves survival compared with cyclosporine alone. Cyclosporine has also been used with some success for the treatment of moderate to severe, acute graft-vs-host disease following bone marrow transplantation. Limited data suggest that cyclosporine may be as effective as corticosteroid therapy. Corticosteroids are generally considered the initial therapy of choice for the treatment of acute graft-vs-host disease.

Rheumatoid Arthritis

Oral cyclosporine is used in the management of the active stage of severe rheumatoid arthritis in selected adults who have an inadequate therapeutic response to methotrexate; the drug may be used in combination with methotrexate in those who do not respond adequately to methotrexate monotherapy. Oral cyclosporine also has been useful in the treatment of rheumatoid arthritis in adults who had an insufficient therapeutic response to, or who did not tolerate nonsteroidal anti-inflammatory agents (NSAIAs) and other disease-modifying antirheumatic drugs (DMARDs) (e.g., gold compounds, penicillamine). Cyclosporine is one of several DMARDs that can be used when DMARD therapy is appropriate. (For further information on the treatment of rheumatoid arthritis, .)

In a placebo-controlled study, cyclosporine administered for 6 months was more effective than placebo in decreasing the number of painful and tender or swollen joints. Results of an uncontrolled clinical study of patients treated with cyclosporine for a median of 29 months showed in comparison to baseline articular index that at 18 months pain (as rated on a visual analog scale) and the duration of morning stiffness were decreased, while functional capacity (as rated on a visual analog scale) was improved. After 24 months of therapy, articular index, pain, and duration of morning stiffness remained decreased. Although few comparative studies with other DMARDs have been published, cyclosporine appears to be as effective as azathioprine, chloroquine, or methotrexate in the management of rheumatoid arthritis. Cyclosporine, azathioprine, and methotrexate did not differ in global assessment of efficacy based on the number of clinical and laboratory variables that improved after 1 year of therapy. The decrease in the number of swollen joints did not differ between cyclosporine and chloroquine after 24 weeks of therapy with either drug as the initial DMARD. The difference between groups in radiologic evidence of progression of disease, as indicated by the increase in the number of target joints with juxtaarticular erosions at 12 months compared with baseline, favored patients who were receiving cyclosporine over the controls who were receiving another DMARD (e.g., chloroquine, hydroxychloroquine, sulfasalazine, auranofin, parenteral gold compounds, penicillamine).

Combined use of cyclosporine and methotrexate appears to improve therapeutic response in patients with rheumatoid arthritis that had improved partially with methotrexate alone. After 6 months of therapy, improvement in the tender-joint count was greater with combined cyclosporine (mean dosage: 3 mg/kg daily) and methotrexate than with methotrexate alone. In addition, more patients treated with cyclosporine and methotrexate had improvement in rheumatoid arthritis, based on criteria of the American College of Rheumatology (i.e., improvement by at least 20% in the number of tender joints, number of swollen joints, and in 3 of 5 other clinical measures including pain, physician's global assessment, patient's global assessment, degree of disability, erythrocyte sedimentation rate). Complete blood cell count and liver function should be monitored at least monthly in patients receiving cyclosporine and methotrexate therapy concomitantly.

Psoriasis

Oral cyclosporine is used in immunocompetent adults with severe (i.e., extensive and/or disabling), recalcitrant plaque psoriasis that is not adequately responsive to at least one systemic therapy (e.g., retinoids, methotrexate, psoralen and UVA light [PUVA therapy]) or in patients for whom other systemic therapy is contraindicated or cannot be tolerated. Discontinuance of therapy with cyclosporine, as with other therapies, will result in relapse of psoriasis in most patients, while rebound occurs rarely.

Crohn's Disease

Cyclosporine has been used in the management of refractory inflammatory, fistulizing, and chronically active Crohn's disease.

Efficacy of cyclosporine has been evaluated in several uncontrolled studies in patients with refractory (e.g., to corticosteroids, anti-infective agents, mercaptopurine, azathioprine, surgery) inflammatory or fistulizing Crohn's disease. In these studies, a limited number of patients with inflammatory or fistulizing disease (who continued to receive anti-infective agents, corticosteroids, azathioprine, mercaptopurine, and/or mesalamine) initially received a continuous IV infusion of cyclosporine over 24 hours (4 mg/kg daily for about 2-10 days) until clinical response (complete response in inflammatory disease usually was defined as resolution of diarrhea and abdominal pain, while partial response was defined as a decrease in stool frequency and/or abdominal pain; complete response in fistulizing disease was defined as closure of the fistulas and cessation of drainage, while partial response was defined as reduction in the size, drainage, and discomfort associated with fistulas) was achieved. About 78-88% of patients responded while receiving IV cyclosporine and 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. However, only about 29-71% of the patients who responded to IV cyclosporine, continued to respond while receiving oral cyclosporine and in 1 study (patients receiving oral cyclosporine for a median of 10.5 weeks), 71% of patients who responded to IV cyclosporine, relapsed after discontinuance of cyclosporine therapy. Some clinicians suggest, however, that a short course (about 4-6 months) of therapy with cyclosporine (administered as an IV infusion initially and followed by an oral course of the drug) given concomitantly with mercaptopurine or azathioprine (drugs associated with long-term improvement in fistulizing Crohn's disease) may be effective in some patients with refractory inflammatory or fistulizing Crohn's disease. Because both mercaptopurine and azathioprine have a slow onset of action (17 weeks or more) and cyclosporine has a faster onset, such an overlap of therapies (for about 4 months) may be beneficial in the fistulizing disease; however, additional well-controlled studies are needed to evaluate the clinical efficacy of these combinations. It also should be considered, that IV administration of cyclosporine may be associated with severe adverse effects and many clinicians state that the drug should be reserved for the management of severe refractory disease.

Results of several uncontrolled and some placebo-controlled trials indicate that oral cyclosporine (5-15 mg/kg daily) has not been consistently effective for inducing or maintaining remission in refractory chronically active Crohn's disease. In a placebo-controlled, double-blind, randomized trial in patients with refractory, chronically active Crohn's disease, clinical improvement has been reported in more patients receiving oral cyclosporine (5-7.5 mg/kg daily) than in those receiving placebo (59% for cyclosporine versus 32% for placebo) at the end of a 3-month treatment period. However, during a subsequent 3-month tapering period, 36 or 55% of patients receiving cyclosporine or placebo, respectively, whose disease improved during the initial 3-month therapy, have relapsed; no substantial difference in disease improvement between cyclosporine therapy and placebo has been observed during the 6-month follow-up period.

For further information about the management of Crohn's disease, .

Ophthalmic Uses

For ophthalmic uses of cyclosporine, .

Other Uses

Cyclosporine potentially may be useful for the treatment of various other conditions that have an immunologic basis.

Cyclosporine also has been used to decrease the frequency of pancreatic or corneal allograft rejection.

Dosage and Administration

Administration

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

Oral Administration

Cyclosporine may be administered orally as the conventional liquid-filled capsules or the conventional oral solution. 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. When exposed to an aqueous environment, Neoral oral solution forms a homogenous transparent emulsion with a droplet size smaller than 100 nm in diameter, which has been referred to as a microemulsion. Gengraf also is described as forming a microemulsion when exposed to an aqueous environment. The 2 commercially available modified oral formulations of cyclosporine, Neoral and Gengraf, have been demonstrated to be bioequivalent to each other.

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.(See Pharmacokinetics: Absorption.) 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.

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. When an oral solution formulation is used, doses of cyclosporine should be measured carefully. A graduated oral syringe is provided for proper measurement of a dose of cyclosporine oral solution formulations. 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. 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. 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; milk should not be used for dilution of the solution since the resultant mixture can be unpalatable. The manufacturers recommend that frequent changing of the diluting beverage be avoided. The diluted solution or emulsion containing cyclosporine should be stirred well and administered immediately, not allowing the mixture to stand before administration. Use of a glass container may minimize adherence of the drug to the walls of the container; styrofoam containers should not be used because they are porous and may absorb the drug. 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. 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. 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. To avoid turbidity, the dosing syringes for Gengraf and Neoral oral solution should not be rinsed with water, alcohol, or other cleaning agents. If the syringes require cleaning, they must be completely dry before reuse. Introduction of water into the product by any means will cause variation in dose.

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. 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, other evidence indicates that such separation in timing may not be adequate, and additional study is needed.(See Drugs and Foods Affecting Hepatic Microsomal Enzymes: Grapefruit Juice, in Drug Interactions.)

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.(See Cautions: Precautions and Contraindications.)Cyclosporine concentrate for injection must be diluted prior to IV infusion. 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. Diluted solutions that have not been administered within 24 hours should be discarded. The required dose of diluted solution is infused over 2-6 hours.

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.

Dosage

Transplant Recipients

Dosage of cyclosporine should be individualized. 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. 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. Therefore, the type of assay used (See Pharmacokinetics), organ transplanted, time since transplantation, other immunosuppressive agents administered concurrently, and other factors are important considerations in the assessment of cyclosporine blood concentrations. 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. 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.

Laboratory Monitoring

Most clinicians currently base monitoring on trough (predose) concentrations of the drug. 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. While most recent experience has been with assays that are specific for unchanged cyclosporine (See Pharmacokinetics), data are accumulating on the use of total drug (both cyclosporine and metabolites) concentrations, and some centers may have switched to such monitoring methods. The frequency of monitoring depends in part on the time that has elapsed since transplantation, intercurrent illness, and concomitant drugs. 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. 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. 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. Results obtained with various methods are not interchangeable, and specialized references and/or the assay manufacturer's labeling should be consulted for interpretative guidelines.

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. Periodic determination of blood or plasma cyclosporine concentrations and adjustment in dosage, when necessary, are especially important in patients, particularly hepatic allograft recipients, receiving long-term oral therapy since absorption of the drug may be erratic.

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. 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). Nonspecific assay methods that detect both unchanged drug and its metabolites also are available, 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. 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. Although several assays and assay matrices are available, the current consensus is that assays specific for unchanged cyclosporine correlate best with clinical events. Such assays include HPLC, monoclonal antibody RIAs, monoclonal antibody FPIA, and EMIT, which have sensitivity and are reproducible and convenient.

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. 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. Administration of even lower initial dosages (e.g., 10-14 mg/kg daily) is the trend for renal allotransplantation. 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. In several studies, pediatric patients have required and tolerated higher dosages. 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.

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

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). After conversion to the modified oral formulation, the increase in trough blood concentrations may be more pronounced and clinically important in some patients. The initial dosage subsequently should be adjusted to attain trough blood concentrations that are similar to those achieved with the conventional oral formulation. However, attainment of therapeutic trough blood concentrations will result in greater exposure (AUC) to cyclosporine than would occur with the conventional oral formulation. 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. 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. The dosage must be adjusted appropriately if trough blood concentrations are outside of the range desired and/or if the measures of safety worsen.

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. 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. Patients tend to have higher blood cyclosporine concentrations after conversion to the modified oral formulations. The higher bioavailability of cyclosporine from the modified oral formulations may result in excessive trough blood concentrations after conversion to these formulations. Clinicians should be particularly cautious with conversional dosages exceeding 10 mg/kg daily. Individual titration of the dosage should be guided by trough blood concentrations, tolerability, and clinical response. 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.

In patients unable to take the drug orally, cyclosporine may be administered by IV infusion at about one-third the recommended oral dosage. 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. 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. Pediatric patients may require higher dosages. Patients should be switched to an oral formulation of cyclosporine as soon as possible after surgery.

Concomitant Corticosteroid Therapy

For the prevention of allograft rejection, the manufacturer states that corticosteroid therapy should always be used concomitantly with IV cyclosporine. For the prevention of allograft rejection, the manufacturers recommend that corticosteroid therapy be administered concomitantly with conventional (nonmodified) oral formulations and be administered concomitantly, at least initially, with the modified oral formulations. Dosage of corticosteroids should be adjusted individually according to the clinical situation. Various schedules to taper corticosteroid dosage appear to yield similar results. 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. Corticosteroid dosage may be tapered further based on individual consideration of patient status and allograft function. 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.

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. 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. If rejection continues after two 3-day courses of therapy, switching the patient to therapy with azathioprine and corticosteroids should be considered. 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. If necessary, courses of methylprednisolone therapy may be repeated until a total dosage of 6 g has been administered. If rejection continues, cyclosporine should be discontinued and switching the patient to therapy with azathioprine and corticosteroids should be considered.

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. Therapeutic response in patients with rheumatoid arthritis generally is apparent after 4-8 weeks of therapy. 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. Lack of benefit by the 16th week of therapy should be considered a therapeutic failure and cyclosporine should be discontinued. Therapy with salicylates, other nonsteroidal anti-inflammatory agents (NSAIAs), or oral corticosteroids may be continued during cyclosporine therapy. 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%. Cyclosporine should be discontinued if adverse effects are severe or do not respond to reduction of dosage.

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. 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. There currently is only limited experience with long-term treatment of rheumatoid arthritis with the modified oral cyclosporine formulations. Following discontinuance of the drug, control of rheumatoid arthritis usually wanes within 4 weeks.

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. 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. Hypertension that develops during therapy with cyclosporine should elicit reduction of the dosage by 25-50%. Persistent hypertension should be managed by further reduction of the dosage of cyclosporine or use of antihypertensive agents. Withdrawal of cyclosporine generally results in return of blood pressure to baseline. 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. Monthly evaluation with complete blood cell count and liver function tests is recommended in patients who also are receiving methotrexate concomitantly with cyclosporine.

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. This dosage should be continued for at least 4 weeks unless prohibited by adverse effects. Some improvement in clinical manifestations of psoriasis generally is observed after 2 weeks of therapy. 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. Dosage may be increased in these increments to a maximum of 4 mg/kg daily based on the patient's tolerance and response.

Cyclosporine may not produce satisfactory control and stabilization of psoriasis until after 12-16 weeks of therapy. 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. 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.

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. A satisfactory response was maintained in 60% of patients in clinical studies with dosages at the lower end of the recommended range. Dosages less than 2.5 mg/kg daily also may be equally effective.

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%. Cyclosporine should be discontinued if adverse effects are severe or do not respond to reduction of the dosage.

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. Rebound does not occur in most patients after withdrawal of cyclosporine. Transformation of chronic plaque psoriasis to more severe forms of psoriasis that included pustular and erythrodermic psoriasis reportedly has occurred in some patients. 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. Strategies in the long-term management of psoriasis should include consideration of alternation of cyclosporine with other therapies.

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. Physical examination should include evaluation for the presence of occult infection because cyclosporine is an immunosuppressive agent. The patient also should be evaluated for the presence of tumors at this initial examination and throughout therapy with cyclosporine. A biopsy should be obtained from dermatologic lesions that do not typify psoriasis before therapy with cyclosporine commences. 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.

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. Hypertension may occur at recommended dosages, with risk increased as the dosage and duration of therapy with the drug increases. 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. Cyclosporine should be withdrawn if hypertension fails to respond to multiple reductions in dosage. Antihypertensive therapy of patients being managed for hypertension prior to initiation of cyclosporine therapy should be adjusted for effectiveness during cyclosporine therapy. When adequate adjustment of antihypertensive therapy is not possible or is not tolerated, cyclosporine should be withdrawn.

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. Serum creatinine must be monitored frequently. 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. When the serum creatinine concentration exceeds baseline by 25% or more, repeated measurement should be obtained within 2 weeks. 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. Such reduction of the dosage also is necessary if serum creatinine concentration exceeds baseline by 50% or more at any time. If the serum creatinine concentration does not decrease to within 25% of baseline after the dosage was modified twice, the drug should be withdrawn. 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.

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. Mild hypomagnesemia and hyperkalemia that are asymptomatic and increases in the serum concentration of uric acid may occur with cyclosporine. Serum concentrations of triglycerides or cholesterol may be increased modestly during therapy with cyclosporine. The dosage of cyclosporine should be reduced by 25-50% in response to any abnormality of clinical concern.

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

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

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. 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. Reversibility of these changes generally occurred with timely reduction of the dosage or withdrawal of cyclosporine. Elevation of serum creatinine concentration increases in frequency and severity as the dosage of cyclosporine and its duration of administration increase. Maintenance of the regimen is likely to result in more pronounced increases in serum creatinine concentration.

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. 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. 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. Elevation of serum creatinine concentration increases in frequency and severity as the dosage of cyclosporine and its duration of therapy increase. Maintenance of the regimen is likely to result in more pronounced increases in serum creatinine concentration that may lead to irreversible renal damage. 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.

Renal Effects

The most frequent and clinically important adverse effect of cyclosporine is nephrotoxicity. 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. 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. Clinical manifestations of cyclosporine-induced nephrotoxicity may include fluid retention, dependent edema, and, in some cases, a hyperchloremic, hyperkalemic metabolic acidosis. The risk of cyclosporine-induced nephrotoxicity may be increased in patients receiving other potentially nephrotoxic agents. (See Drug Interactions: Nephrotoxic Drugs.) Mild cyclosporine-induced nephrotoxicity generally occurs within 2-3 months after transplantation. 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. 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; these elevations usually respond to dosage reduction.

Differentiation of Nephrotoxicity and Allograft Rejection

In patients with renal allografts, acute episodes of allograft rejection must be differentiated from nephrotoxic effects of cyclosporine. 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. Although reliable and sensitive differentiation of cyclosporine-induced nephrotoxicity from renal allograft rejection through specific diagnostic criteria currently is not possible, and nephrotoxicity and rejection may coexist in up to 20% of patients, 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. For example, nephrotoxicity from cyclosporine has been associated with a history of having undergone a transplant involving prolonged kidney preservation time or prolonged anastomosis time, having received concomitant therapy with nephrotoxic drugs (e.g., an aminoglycoside, a nonsteroidal anti-inflammatory agent), or having received an organ from a donor who was older than 50 years of age or who was hypotensive, whereas renal allograft rejection has been associated with a history of antidonor immune response or previous renal allotransplantation. Nephrotoxicity often becomes apparent clinically more than 6 weeks postoperatively in patients whose allograft functioned initially or as prolonged initial nonfunction of the allograft that resembles acute tubular necrosis, whereas renal allograft rejection often becomes apparent clinically less than 4 weeks postoperatively and manifests with signs such as fever exceeding 37.5°C, swelling and tenderness of the graft, weight gain exceeding 0.5 kg, and a decrease in daily urine volume by more than 500 mL or 50%.

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. 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. 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.(See Pharmacokinetics.) 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. 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. 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.

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, and a ratio of blood urea nitrogen (BUN) to serum creatinine of at least 20. 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, or a BUN to creatinine ratio of less than 20.

The histologic features of allograft biopsies in patients with cyclosporine-induced nephrotoxicity include effects on the arterioles, tubules, and interstitium. Such findings include arteriolopathy manifested as medial hypertrophy and hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, and progressive scarring. Renal tubular effects of nephrotoxicity include atrophy, isometric vacuolization, and isolated calcifications. Interstitial effects of nephrotoxicity include minimal edema, mild focal infiltrates of mononuclear cells, and diffuse interstitial fibrosis that often is the striped form. The histologic features of allograft biopsies in patients with rejection include effects on the arterioles and arteries, tubules, interstitium, and glomeruli. Such findings include endovasculitis manifested as arteriolar and arterial endothelial cell proliferation, intimal arteritis, fibrinoid necrosis, and sclerosis. Renal tubular effects of rejection include tubulitis with erythrocyte and leukocyte casts and some irregular vacuolization. Interstitial effects of rejection include a diffuse moderate to severe infiltrate of mononuclear cells, edema, and hemorrhage. Glomerulitis, manifested as infiltration of glomerular capillaries by mononuclear cells, is associated with rejection. 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.

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; urine cytology reveals tubular cells with vacuolization of cytoplasm and granularization. Manometry shows an intracapsular pressure of less than 40 mm Hg, and ultrasonography shows the renal cross-sectional area to be unchanged. 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; HLA-DR antigens are expressed strongly by these mononuclear cells. Urine cytology in rejection may show degenerative renal tubular cells, plasma cells, and lymphocyturia exceeding 20% of the urinary sediment. Intrarenal manometry shows an intracapsular pressure exceeding 40 mm Hg in many patients with rejection, and ultrasonography shows an increase in graft cross-sectional area; the anteroposterior diameter is equal to or greater than the transverse diameter.

In most patients with nephrotoxicity, magnetic resonance imagery shows normal renal appearance, 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. While the decrease in tubular function is a deteriorative effect, renal perfusion is not decreased to a deleterious extent. With rejection, findings of magnetic resonance imagery include loss of distinct corticomedullary junction, swelling of the allograft, image intensity of parenchyma that approaches the image intensity of psoas, and loss of hilar fat; radionuclide scans may show patchy arterial flow. 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; uptake of indium In 111-labeled platelets or technetium Tc 99m in colloid is increased.

Limited data suggest that some of the variables associated with nephrotoxicity actually may be risk factors for the development of nephrotoxicity from cyclosporine. 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). 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, 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. Some patients with chronic nephrotoxicity did not exhibit acute cyclosporine-induced deterioration of renal function. 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.

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. 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.

A form of cyclosporine-associated nephropathy that is characterized by serial deterioration in renal function and changes in renal morphology also has been described. 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. 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. The morphologic changes include renal tubular vacuolization, tubular microcalcifications, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy. 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. Furthermore, renal allografts appear to be most vulnerable to the toxic effects of cyclosporine during this time. 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. Whether interstitial fibrosis is reversible and its correlation to renal function are not known. Arteriolopathy reportedly was reversible when the dosage of cyclosporine was decreased or therapy with the drug was discontinued.

Management of Nephrotoxicity

Gradual reduction of cyclosporine dosage is recommended for the management of nephrotoxicity, with careful patient assessment for several days to weeks. 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. Concomitant use of corticosteroids with cyclosporine does not appear to improve renal function.

Other Renal Effects

Hyperkalemia (that may be associated with hyperchloremic metabolic acidosis), hypomagnesemia, and decreased serum bicarbonate concentration have been reported frequently in patients receiving cyclosporine; these effects may result from nephrotoxic effects of the drug. Hyperuricemia also occurs commonly in cyclosporine-treated patients, particularly in those receiving diuretics concurrently, and may result in gout in some patients. Although not clearly established, hyperuricemia appears to result at least in part from decreased renal clearance of uric acid. Hematuria has occurred rarely in patients receiving cyclosporine.

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. Elevated serum creatinine concentrations occurred in about 20% of patients. 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. 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. 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. 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. 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. Biopsies occasionally showed kidneys with structural damage manifested as renal tubular atrophy, interstitial fibrosis, and hyaline arteriolopathy that were graded as moderate. Mild tubulointerstitial scarring and glomerulosclerosis were observed in the other patients but a relationship to cyclosporine was not certain. 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. 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.

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. Maintenance of the regimen is likely to result in more pronounced increases in serum creatinine concentration that may lead to irreversible renal damage. The maximal increase in serum creatinine concentration may be a predictor of nephropathy from cyclosporine. Features suggesting nephropathy were observed in the renal biopsies of some patients with rheumatoid arthritis treated with cyclosporine for an average of 19 months. The dosage was 4 mg/kg daily or less in one of the patients. Dosage reduction or withdrawal of cyclosporine resulted in improvement in serum creatinine concentrations in most of these patients. 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. 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. 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. 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. Cyclosporine administered to treat rheumatoid arthritis resulted in elevated BUN in 1% to less than 3% of patients.

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. 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. 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. Discontinuance of therapy with cyclosporine resulted in normalization of serum creatinine concentration in most patients. 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. 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. Evaluation of biopsies for focal interstitial fibrosis and arteriolar hyaline wall thickening showed increases compared with baseline. The percentage of sclerotic glomeruli was increased compared with baseline after 4 years of therapy with cyclosporine.

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. 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. In some patients with cardiac allografts who developed hypertension while receiving cyclosporine, therapy with hypotensive agents has been required.

Hypertension generally develops within a few weeks after beginning cyclosporine therapy and affects both the systolic and diastolic blood pressure. Although the mechanism has not been clearly established, there is some evidence that hypertension may result from the renal vasoconstrictive effects of the drug. The manufacturers state that hypertension associated with cyclosporine therapy may respond to dosage reduction and/or antihypertensive therapy. However, some evidence from clinical studies suggests that response to antihypertensive therapy may be variable and that elevations in diastolic blood pressure may be more resistant to treatment than elevations in systolic pressure.

Myocardial infarction has occurred rarely in patients receiving the drug.

Cyclosporine administered to treat rheumatoid arthritis resulted in hypertension in up to about 26% of patients. 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. Arrhythmia occurred in up to about 5% of patients. Abnormal heart sounds, cardiac failure, myocardial infarction, and peripheral ischemia each occurred in 1% to less then 3% of patients.

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.

Nervous System Effects

Adverse nervous system effects occur frequently in patients receiving cyclosporine. Tremor reportedly occurs in 12-21, 31, or 55% of patients with kidney, heart, or liver allografts, respectively, who receive cyclosporine. In one study in renal allograft recipients, however, tremor occurred in about 40% of cyclosporine-treated patients. 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.

Seizures (particularly when cyclosporine was used in combination with high-dose corticosteroids), headache, paresthesia, hyperesthesia, flushing, and confusion have been reported occasionally in patients receiving cyclosporine. There is some evidence that cyclosporine-induced seizures and other neurotoxicity may be associated with high blood or plasma concentrations of the drug, concurrent high-dose corticosteroid therapy, hypertension, and/or hypomagnesemia. 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). Adverse neurologic effects in most cases are reversible upon discontinuance of the drug or in some patients following dosage reduction.

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.

Psychiatric disorders including anxiety, flat affect, and depression have occurred rarely in patients receiving the drug.

Cyclosporine administered to treat rheumatoid arthritis resulted in headache in up to about 25% of patients. Tremor or paresthesia occurred in up to about 13 or 11% of patients, respectively. Dizziness, depression, flushing, insomnia, or migraine occurred in up to about 8, 6, 5, 4, or 3% of patients, respectively. Hypoesthesia, neuropathy, and vertigo each occurred in 1% to less than 3% of patients. Psychiatric disorders that occurred in 1% to less than 3% of patients include anxiety, impaired concentration, confusion, emotional lability, decreased libido, increased libido, nervousness, paroniria, and somnolence.

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

Dermatologic Effects

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

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

Acne and brittle and abnormal fingernails occur occasionally in patients receiving cyclosporine.

Cyclosporine administered to treat rheumatoid arthritis resulted in hypertrichosis or rash in up to about 19 or 12% of patients. Alopecia, gingival hyperplasia, or gingivitis each occurred in up to about 4% of patients. Bullous eruption or skin ulceration each occurred in up to about 1% of patients. Angioedema, dermatitis, dry skin, eczema, folliculitis, gingival bleeding, nail disorder, abnormal pigmentation, pruritus, skin disorder, and urticaria each occurred in 1% to less than 3% of patients.

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

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. 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. Reduction of cyclosporine dosage usually reverses the hepatotoxic effects of the drug; in one study, hepatotoxicity was associated with trough serum concentrations (determined by RIA) greater than 1000 ng/mL. Although increased serum alkaline phosphatase concentration has also been reported, it appears to be from bone rather than liver origin.

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

GI Effects

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

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

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

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. 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. 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.

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

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

Hematologic Effects

Adverse hematologic effects of cyclosporine reportedly occurring occasionally include leukopenia, anemia, and thrombocytopenia. 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. 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, and such findings are generalizable to other immunosuppressive agents used after transplantation. 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. Neither the pathogenesis nor optimal management of the syndrome are clear. 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. Lymphoma has also occurred occasionally.(See Cautions: Mutagenicity and Carcinogenicity.) Evidence from animal studies and clinical studies in humans indicates that cyclosporine does not appear to depress bone marrow function. In one study, bone marrow depression occurred in 12% of patients receiving azathioprine and corticosteroids but did not occur in cyclosporine-treated patients. In another study, leukopenia (leukocyte count less than 2000/mm) occurred in only one cyclosporine-treated patient while it occurred in about 10% of patients receiving azathioprine and corticosteroids.

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

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

Sensitivity Reactions

Sensitivity reactions (including anaphylaxis) have reportedly occurred in 2% or less of patients receiving cyclosporine. Anaphylaxis has been reported in 0.1% of patients receiving the drug IV. 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); in addition, some patients who developed anaphylaxis while receiving the drug IV subsequently received the conventional oral solution without unusual adverse effect. Anaphylactic reactions to IV cyclosporine include flushing of the face and upper thorax, acute respiratory distress with dyspnea and wheezing, hypotension, tachycardia, and, rarely, death. 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. Polyoxyl 35 castor oil has been shown to cause anaphylactoid reactions in animals, including stimulation of histamine release and a hypotensive effect; death has occurred in some animals. An immunologic mechanism (e.g., antibody production, complement activation) has been suggested in some studies and case reports; it has also been suggested that polyoxyl 35 castor oil may enhance the immunogenicity of other agents such as drugs. Anaphylactic reactions have been associated with administration of other drugs in a polyoxyl 35 castor oil-containing vehicle; 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. Although IV cyclosporine-induced anaphylactic reactions may subside in some patients when IV infusion of the drug is stopped, death resulting from respiratory arrest and aspiration pneumonia has occurred in at least one patient.

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

Other Adverse Effects

Hyperlipidemia and abnormalities in electrophoresis may occur in patients receiving IV cyclosporine, since the vehicle in the commercially available cyclosporine concentrate for injection (polyoxyl 35 castor oil) has been associated with the development of these effects. 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.

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

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

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

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

Precautions and Contraindications

Cyclosporine should be used for therapeutic applications other than transplantation only by clinicians experienced in such use of immunosuppressive therapy. 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. 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. 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. Although patients who are stabilized on cyclosporine may receive the drug as outpatients, periodic laboratory monitoring is required. The clinician responsible for cyclosporine maintenance therapy should have complete information necessary for appropriate follow-up of the patient.

Immunosuppression with cyclosporine may result in increased susceptibility to infection, including serious infections with fatal outcomes, and the possible development of lymphoma.(See Cautions: Mutagenicity and Carcinogenicity.) 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. Because of the increased risk for skin cancer, patients should be advised to limit ultraviolet light exposure. 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. 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. 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.

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. 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. The risk for malignancies may be increased with concurrent use of cyclosporine and other immunosuppressive agents through induction of excessive immunosuppression.

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. 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. 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. A biopsy should be obtained from dermatologic lesions that do not typify psoriasis, before therapy with cyclosporine commences. Cyclosporine should be administered only after suspicious lesions resolve completely and only if other therapies are not an option. 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. In addition, therapy with coal tar should not be administered concurrently with cyclosporine.

Immunosuppressed patients are at an increased risk for opportunistic infections, including reactivation of latent viral infections. These include BK virus-associated nephropathy (BKVN), which has been reported in patients receiving immunosuppressants, including cyclosporine, mycophenolate, sirolimus, and tacrolimus. Primary infection with polyoma BK virus typically occurs in childhood; following initial infection, the virus remains latent, but reactivation may occur in immunocompromised patients. 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. 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. Patients should be monitored for possible signs of BKVN, including deterioration in renal function, during therapy with cyclosporine; screening assays for polyomavirus replication also have been recommended by some clinicians. Early intervention in patients who develop BKVN is critical; a reduction in immunosuppressive therapy should initially be considered in such patients. 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.

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. The presence of these conditions also contraindicates therapy with cyclosporine to manage rheumatoid arthritis.

Because of the risk of anaphylaxis (see Cautions: Sensitivity Reactions), IV cyclosporine should be reserved for patients unable to tolerate oral formulations of the drug. 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. 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. If anaphylaxis occurs, IV infusion of cyclosporine should be discontinued immediately and the patient given appropriate therapy (e.g., epinephrine, oxygen) as indicated.

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]).

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. 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. However, monitoring of blood or plasma concentrations of cyclosporine is not a substitute for renal function monitoring or tissue biopsies. 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. Monitoring of blood or plasma cyclosporine concentrations may be especially important in hepatic allograft recipients, 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. In addition, patients with GI malabsorption syndromes may have difficulty in achieving therapeutic blood or plasma concentrations when the drug is administered orally. 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.

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. 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. 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, and that any change in oral formulation of the drug requires the supervision of a clinician and should be done cautiously.

At high dosages, cyclosporine may cause nephrotoxicity and/or hepatotoxicity. 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. 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. 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.(See Cautions: Renal Effects.) 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 therapy 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.

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. Nephrotoxicity may occur at recommended dosages, with increasing risk as the dosage and duration of therapy with the drug increases. The serum creatinine concentration and BUN may increase in patients receiving cyclosporine, reflecting a decrease in the glomerular filtration rate. The maximal increase in serum creatinine concentration may be a predictive factor for cyclosporine-induced nephropathy. 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. Geriatric patients should be monitored with particular care because renal function also decreases with age. 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. Elevated serum creatinine concentrations generally reverse upon timely cyclosporine dosage reduction or disontinuance. 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.

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; the modified oral formulations have been used in children as young as 1 year of age. Cyclosporine has been used in hepatic and renal allograft recipients 7.5 months to 18 years of age. 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; however, some clinicians have reported an increased frequency of seizures, possibly related to concomitant hypertension or high-dose corticosteroid therapy, in children receiving cyclosporine. The possibility that serious nephrotoxicity, hypertension, and/or seizures may occur in children receiving the drug should be considered.

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.

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. Patients 65 years of age or older were more likely to develop systolic hypertension while receiving cyclosporine to treat rheumatoid arthritis in clinical studies. 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.

Mutagenicity and Carcinogenicity

Various tests have not shown cyclosporine to be mutagenic. 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. However, in an in vitro study that used human lymphocytes, high concentrations of cyclosporine appeared to induce sister chromatid exchange.

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. 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. In these studies, cyclosporine was administered in doses 0.01-0.16 times the maintenance dose for humans. The development of hepatocellular carcinomas and pancreatic islet cell adenomas in mice and rats did not appear to be dose related.

An increase in the incidence of malignancy is a recognized complication of immunosuppression in allograft recipients and patients with psoriasis or rheumatoid arthritis. Skin cancers and non-Hodgkin's lymphoma develop most commonly. Lesions may regress after reduction or discontinuance of immunosuppression. 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.

Lymphomas have developed in patients receiving cyclosporine alone or in combination with other immunosuppressive agents, and some patients have developed a lymphoproliferative disorder that resolved following discontinuance of the drug. The lymphomas and lymphoproliferative disorders appear to be associated with Epstein-Barr virus (EBV) infections. It has been suggested that cyclosporine may cause alteration of the antibody for EBV or may inhibit the cell-mediated response to EBV, resulting in the development of lymphoma. 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. 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. 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.

Although the risk of lymphoma appears to be greatest when there is substantial immunosuppression (i.e., concomitant use of multiple immunosuppressive agents), all immunosuppressed patients should be considered at risk for developing lymphoma. The nature and optimum management of posttransplant lymphomas and lymphoproliferative disorders in allograft recipients remain to be clearly established, 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. In one study, reduction of cyclosporine and/or prednisone dosage resulted in resolution of lymphomas but was not associated with allograft rejection. Squamous cell carcinoma occurred in one patient receiving cyclosporine following renal transplantation but has not been directly attributed to the drug.

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

Patients receiving cyclosporine to treat psoriasis have developed malignancies, especially of the skin. Squamous cell carcinoma or basal cell carcinoma occurred in 0.9 or 0.4% of patients, respectively, who received the drug. In another aggregate of clinical studies, tumors were reported in about 2% of patients who received the drug. Malignancies of the skin that included squamous cell and basal cell carcinomas were reported in about 1% of patients who received cyclosporine. Most of these patients had been treated previously with PUVA and some had received prior therapy with methotrexate, coal tar, or UVB. 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. 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. 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. Malignancies that involved various organs accounted for the rest of the patients affected to yield an incidence of about 1%. During postmarketing surveillance, several more patients were reported to have developed tumors while receiving cyclosporine for psoriasis. Cervical intra

Drug Interactions

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. If concomitant use of cyclosporine with such drugs is unavoidable, renal function should be monitored carefully.

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

Concomitant administration of cyclosporine and amphotericin B has produced additive nephrotoxicity. 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. 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; this reduction in cyclosporine dosage may decrease the risk of nephrotoxicity while maintaining adequate immunosuppression.

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. Therefore, administration of aminoglycosides should be avoided in renal allograft recipients who are receiving cyclosporine.

Concomitant administration of cyclosporine and co-trimoxazole has resulted in increases in serum creatinine concentrations. 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.

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. 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. Creatinine clearance differed between indomethacin and acetaminophen but the increase of 6% observed with acetaminophen compared with indomethacin was not considered clinical in magnitude.

Concomitant administration of cyclosporine and diclofenac may increase the nephrotoxic potential of cyclosporine. In addition to increases in serum creatinine concentration, increased serum potassium concentrations and/or blood pressure have occurred in some patients receiving the drugs concomitantly. 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. 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. Pharmacokinetic interactions of clinical importance have not been observed between cyclosporine and aspirin, indomethacin, ketoprofen, or piroxicam. 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.

Concomitant administration of cyclosporine and colchicine may increase concentrations of cyclosporine, resulting in additive nephrotoxic effects. Cyclosporine also may reduce clearance of colchicine increasing the potential for enhanced colchicine toxicity (myopathy, neuropathy), particularly in patients with renal impairment. 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.

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 lymphoma(see Cautions: Mutagenicity and Carcinogenicity) and susceptibility to infection 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. 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. The manufacturers state that patients with psoriasis should not receive cyclosporine concomitantly with other immunosuppressive agents since excessive immunosuppression may result.

Concomitant administration of cyclosporine and sirolimus substantially increases blood sirolimus concentrations. Sirolimus should be given 4 hours following cyclosporine administration to minimize the effect on sirolimus concentrations. 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.

Concomitant administration of cyclosporine and methotrexate resulted in elevation of the AUC of methotrexate in patients with rheumatoid arthritis. 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. However, the clinical importance of these observations is not known. Blood concentrations of cyclosporine did not appear to be affected by coadministration of cyclosporine and methotrexate.

Potassium-sparing Drugs

Because cyclosporine may cause hyperkalemia, the manufacturers state that the drug should not be used concomitantly with potassium-sparing diuretics. 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.

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. Drugs and foods that inhibit hepatic microsomal enzymes could decrease the metabolism of cyclosporine and increase its concentration in biologic fluid. 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. Drugs that induce cytochrome P-450 activity could increase the metabolism of cyclosporine and decrease its concentration in biologic fluid. This potential interaction has been well substantiated to occur between cyclosporine and nafcillin, rifampin, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, octreotide, sulfinpyrazone, terbinafine, or ticlopidine. In addition, clinicians should be cautious about concurrent administration of cyclosporine with rifabutin. 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. 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.

Azole-derivative Antifungal Agents

Concomitant administration of cyclosporine and ketoconazole has been reported to increase plasma concentrations of cyclosporine and serum creatinine concentrations. It has been suggested that ketoconazole may interfere with the metabolism of cyclosporine via hepatic microsomal enzyme inhibition, although other mechanisms may also be involved. 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. Patients stabilized on both drugs may require an increase in cyclosporine dosage when ketoconazole is discontinued.

Concomitant administration of cyclosporine and fluconazole has been reported to increase whole blood concentrations of cyclosporine, and such increase may be associated with nephrotoxic effects. 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. However, such changes were not observed in several other patients receiving fluconazole 100 or 200 mg daily. Increases in trough cyclosporine concentrations and serum creatinine concentration also occurred when fluconazole dosage was increased from 100 to 300 mg daily. Evidence suggests that fluconazole interferes with the metabolism of cyclosporine via hepatic microsomal enzyme inhibition.

Concomitant administration of cyclosporine and itraconazole has been reported to increase whole blood or serum concentrations of cyclosporine and serum creatinine concentrations. Evidence indicates that itraconazole competitively inhibits the hydroxylation of cyclosporine via hepatic microsomal enzyme inhibition.

Concomitant administration of cyclosporine and voriconazole also may increase blood or plasma cyclosporine concentrations.

Macrolides

Concomitant use of cyclosporine and erythromycin may result in substantial increases in blood or plasma concentrations of cyclosporine and subsequent signs of cyclosporine toxicity (e.g., nephrotoxicity). Studies in healthy adults indicate that erythromycin can substantially decrease plasma clearance of cyclosporine, presumably by inhibiting hepatic metabolism of the drug, although the exact mechanism remains to be clearly determined. Cyclosporine and erythromycin should be used concomitantly with caution, and patients should be monitored for evidence of cyclosporine toxicity. 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.

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

Corticosteroids

Concomitant administration of prednisolone with cyclosporine may result in decreased plasma clearance of prednisolone, and plasma concentrations of cyclosporine may be increased during concomitant therapy with cyclosporine and methylprednisolone. In addition, seizures have reportedly occurred in adult and pediatric patients receiving cyclosporine and high-dose corticosteroid therapy concurrently with cyclosporine. The mechanism for this interaction may involve competitive inhibition of hepatic microsomal enzymes. 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.

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. 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.

Concomitant administration of cyclosporine and verapamil has resulted in increased whole blood concentrations of cyclosporine. It has been suggested that verapamil may interfere with metabolism of cyclosporine via hepatic microsomal enzyme inhibition. 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.

Concomitant administration of cyclosporine and nicardipine has resulted in increased whole blood or plasma cyclosporine concentrations. Concomitant administration of cyclosporine and nifedipine resulted in more frequent occurrence of gingival hyperplasia compared with cyclosporine alone.

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

Other Drugs Affecting Hepatic Microsomal Enzymes

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

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. An increase in whole blood concentrations of cyclosporine occurred with concomitant administration of cyclosporine, cimetidine, and metronidazole. Concomitant administration of cyclosporine and ranitidine also has resulted in an increase in serum creatinine concentrations. However, some evidence indicates that serum creatinine concentration, creatinine clearance, and inulin clearance are affected minimally by the combination of cyclosporine and ranitidine.

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

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.(See Drugs and Foods Affecting Hepatic Microsomal Enzymes: Calcium-Channel Blocking Agents, in Drug Interactions.)

Concomitant use of cyclosporine and allopurinol has resulted in increases in the whole blood concentration of cyclosporine. Serum creatinine concentration may also be elevated. Concomitant administration of cyclosporine and danazol also has resulted in increased blood cyclosporine concentrations and serum creatinine concentrations.

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. 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.

Grapefruit Juice

Concomitant oral administration of grapefruit juice with cyclosporine has been reported to increase bioavailability of the drug. The interaction does not appear to occur with sweet (''common'') orange juice, but some evidence indicates that it is likely with sour (Seville) orange juice.

In several studies in healthy adults or renal transplant recipients receiving cyclosporine as conventional (nonmodified) oral capsules with 175-250 mL of oral grapefruit juice, 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, 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. Therefore, additional study is needed to determine whether separation of cyclosporine and grapefruit juice administration during the day can adequately minimize the potential interaction.

The interaction between grapefruit juice and cyclosporine bioavailability appears to result from inhibition, probably prehepatic, of the cytochrome P-450 enzyme system by some constituent(s) in the juice; grapefruit juice does not interfere appreciably with metabolism following IV drug administration. 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, CYP2A6, and the CYP3A subfamily (e.g., CYP3A4); these enzymes are present in the liver and/or extrahepatic tissues such as intestinal mucosa. Following oral administration of cyclosporine, certain benzodiazepines (e.g., midazolam, triazolam), and certain calcium-channel blocking agents (e.g., 1,4-dihydropyridine derivatives), 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.

The constituent(s) of grapefruit juice principally responsible for this interaction has not been elucidated fully. In addition, the composition of grapefruit juice is variable depending on natural and commercial factors. 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). Grapefruit juice contains high concentrations of bioflavonoids, which have been shown to inhibit cytochrome P-450 microsomal enzymes. 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, in vitro and in vivo evidence indicates that this bioflavonoid probably has little or no effect on the inhibition of cytochrome P-450 enzymes. Naringenin, the aglycone metabolite of naringin, is a more potent inhibitor of cytochrome enzymes, but recent evidence suggests that this constituent may only contribute to, not be principally responsible for, grapefruit juice-induced drug interactions. 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. 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). 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. 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.

Cyclosporine concentrations ideally are maintained in a relatively narrow range to prevent transplant rejection and minimize toxicity. 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. 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, others have cautioned that the resultant effects would be unpredictable since the composition of this juice is not standardized. 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, but the manufacturers recommend that concomitant use of these formulations and the juice also be avoided.

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.

Vaccines

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

Other Drugs

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

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. The manufacturer of bosentan states that concomitant use of bosentan and cyclosporine is contraindicated.

Concomitant administration of cyclosporine and digoxin has resulted in decreases in apparent volume of distribution and serum clearance of digoxin. 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. 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.

For information on potential interactions between cyclosporine and NSAIAs, see Drug Interactions: Nephrotoxic Drugs.

Pharmacokinetics

Cyclosporine as unchanged drug is chiefly responsible for immunosuppressive activity, although certain metabolites (e.g., AM1, AM9, AM4N) appear to contribute, at least in part, to this activity. 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). 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. Although the most appropriate biologic fluid and assay method for determining cyclosporine concentrations have not been fully established, most experts currently recommend that whole blood preferably be used 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. 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, although precise relationships remain to be established. In addition, these experts currently recommend that an assay method with high specificity for unchanged cyclosporine preferably be used. Some laboratories may continue to report, and clinicians to use, cyclosporine concentrations determined in plasma or serum, and, while the benefits remain unclear,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. 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. Therefore, all values for cyclosporine concentration must be qualified by the biologic fluid and assay method used, 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.

Distribution of cyclosporine into erythrocytes is temperature and concentration dependent; therefore, reported plasma concentrations are affected by temperature during the separation of plasma and may also be affected by concentration of the drug. 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. Determinations of drug concentration using anticoagulated, hemolyzed whole blood may avoid the problem of temperature-dependent redistribution of the drug between plasma and erythrocytes. Plasma concentrations of the drug may also be affected by the patient's lipoprotein concentration and hematocrit. Following administration of the same dose, blood concentrations of cyclosporine are higher than plasma concentrations since the drug is distributed into erythrocytes. Plasma and serum cyclosporine concentrations are comparable.

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; the 2 assays do not yield comparable results. Both specific (for unchanged drug) and nonspecific RIA methods are available. 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. The ratio of specific (either RIA or HPLC) to nonspecific assays of blood cyclosporine concentrations has varied from 1:1 to 1:8; 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. The ratio may remain constant for fixed points of comparison during the dosing interval. 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. 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). Even with specific immunoassays, some cross-reactivity with cyclosporine metabolites may exist, resulting in slightly different reference ranges for cyclosporine concentrations. 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.

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. 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.

Absorption

Following oral administration, cyclosporine is variably and incompletely absorbed. 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. Absorption of orally administered cyclosporine from conventional (nonmodified) oral formulations reportedly is erratic during long-term therapy. 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.

Peak blood and plasma cyclosporine concentrations occur at about 3.5 hours following oral administration of conventional (nonmodified) formulations of the drug. Following oral administration, cyclosporine is metabolized on first pass through the liver.(See Pharmacokinetics: Elimination.) Although oral bioavailability of cyclosporine administered as conventional oral formulations averages 30% across various allograft recipients, it exhibits considerable interindividual variation, ranging from 2-89%, depending on numerous variables including organ transplant type; in hepatic or renal allograft recipients, estimates range from less than 10% to as high as 89%, respectively. 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. Limited data indicate that the bioavailability of the conventional liquid-filled capsules of cyclosporine is equivalent to that of the conventional oral solution. 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. 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.

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. 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, the AUC of cyclosporine is linearly related to usual doses of the drug administered as the modified oral formulations; a linear relationship also has been described for conventional oral formulations when plasma and HPLC were used. 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. 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. Such a factor makes individualization of dosage necessary for optimal therapy. 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. Some evidence indicates that intraindividual variability in peak and trough blood concentrations of cyclosporine also is less with the modified oral formulations. 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. Intraindividual variabilities in the trough concentration of cyclosporine from modified and conventional oral formulations were 17-30 and 16-38%, respectively, in these patients. Limited data in children also show that the bioavailability of cyclosporine is higher with the modified oral formulations. The modified oral capsules of Neoral are bioequivalent with Neoral oral solution. The modified oral capsules of Gengraf also are bioequivalent with the modified oral solution of Gengraf. In addition, the 2 commercially available modified oral formulations of cyclosporine, Neoral and Gengraf, have been demonstrated to be bioequivalent to each other.

The higher bioavailability of the modified oral formulations relative to the conventional (nonmodified) oral formulation varies across patient populations. 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. In de novo renal transplant patients administered either formulation of cyclosporine, the dose-normalized AUC was 23% greater with the modified oral formulation. 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. 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. 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. 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. 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. Peak blood concentrations are increased by 40-106% in renal transplant patients and by approximately 90% in hepatic transplant patients. Peak blood concentrations of cyclosporine occur from 1.5-2 hours following oral administration of the modified formulations to renal transplant patients.

Food decreases the AUC and peak blood concentration of cyclosporine attained with the modified oral formulations. 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). 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. Similar effects occurred with a low-fat meal (e.g., 667 calories, 15 g of fat). 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). 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.

External biliary diversion in de novo hepatic transplant patients had very little effect on the absorption of cyclosporine from the oral formulation of Neoral. 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. 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 &bul;h/mL at 4 weeks. 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. 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&bul;h/mL. 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. 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&bul;h/mL at 4 weeks. 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.

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&bul;h/mL. 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&bul;h/mL. 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&bul;h/mL. 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&bul;h/mL. 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&bul;h/mL.

Blood or plasma concentrations of cyclosporine required for therapeutic effect or associated with toxicity have not been established precisely.(See introductory paragraphs in Pharmacokinetics.) Organ rejection has reportedly occurred less frequently when trough blood concentrations of the drug (determined by HPLC) were greater than 100 ng/mL. 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. An association between trough serum concentrations (determined by RIA) greater than 500 ng/mL and cyclosporine-induced nephrotoxicity has been reported.

Distribution

Cyclosporine is widely distributed into body fluids and tissues, with most of the drug being distributed outside the blood volume. 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 (Vd) of cyclosporine has been reported to be 13 L/kg. The drug has a volume of distribution at steady-state (Vss) of 3-5 L/kg following IV administration in solid organ allograft recipients. In one study following IV administration of cyclosporine in patients with severely impaired renal function (i.e., creatinine clearance less than 5 mL/minute), Vss ranged from 1.45-7.26 L/kg.

Approximately 90-98% of cyclosporine in plasma is protein bound, mainly to lipoproteins (85-90% of total protein binding). 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). Distribution of the drug in blood is dose dependent; 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. At high concentrations, distribution of cyclosporine into leukocytes and erythrocytes becomes saturated. Concentrations of the drug achieved in mononuclear cells have been reported to be 1000 times greater than those achieved in erythrocytes.

Cyclosporine crosses the placenta in animals and humans. 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.

Cyclosporine is distributed into milk. 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. Studies in animals have shown that cyclosporine is distributed into milk at a maximum concentration of 2% of the maternal dose.

Elimination

Blood concentrations of cyclosporine generally appear to decline in a biphasic manner, although a triphasic disposition also has been described. In adults with normal renal and hepatic function, the half-life in the initial phase (t½α) has been reported to average 1.2 hours and the half-life in the terminal elimination phase (t½β) has averaged 8.4-27 hours (range: 4-50 hours). In one study following IV administration of cyclosporine in patients with severely impaired renal function (i.e., creatinine clearance less than 5 mL/minute), t½β averaged 15.8 or 16.5 hours based on blood cyclosporine concentrations determined by HPLC or RIA, respectively.

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. Clearance of the drug in infants may be up to severalfold higher and in older children twice as high as that in adults. Cardiac transplant patients appear to have slightly slower blood cyclosporine clearance.

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. Limited data are available for pediatric patients. 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. 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. 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. 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. 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. The clearance of cyclosporine reportedly is not changed substantially by renal failure or dialysis.

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. The pharmacologic and toxicologic activities of cyclosporine's metabolites are considerably less than those of the parent drug. The drug undergoes extensive first-pass metabolism following oral administration. Several major metabolic pathways, including hydroxylation of the Cγ-carbon of 2 leucine residues, Cλ-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. Conjugation of these metabolites or hydrolysis of the cyclic peptide chain does not appear to be an important pathway for cyclosporine metabolism. 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. 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. 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. 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.

Cyclosporine is principally excreted via bile, almost entirely as metabolites. Only about 6% of a dose of the drug is excreted in urine, with 0.1% of a dose being excreted unchanged. 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.

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