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All about: Neoral

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Generic Name: cyclosporine
Dosage Form: Soft gelatin capsules and oral solution

T2005-23

     Neoral® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED

     Neoral® Oral Solution (cyclosporine oral solution, USP) MODIFIED

      Rx only

Prescribing Information

Warning

Only physicians experienced in management of systemic immunosuppressive therapy for the indicated disease should prescribe Neoral®. At doses used in solid organ transplantation, only physicians experienced in immunosuppressive therapy and management of organ transplant recipients should prescribe Neoral®. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Neoral®, a systemic immunosuppressant, may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients Neoral® may be administered with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the increase in the degree of immunosuppression in transplant patients.

Neoral® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral®Oral Solution (cyclosporine oral solution, USP) MODIFIED have increased bioavailability in comparison to Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune® Oral Solution (cyclosporine oral solution, USP). Neoral®and Sandimmune® are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, cyclosporine exposure will be greater with Neoral® than with Sandimmune®. If a patient who is receiving exceptionally high doses of Sandimmune® is converted to Neoral®, particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking Neoral® to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assays must be done with detailed knowledge of the assay methods employed.

FOR PSORIASIS PATIENTS (SEE ALSO BOXED WARNINGS ABOVE)

Psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy, are at an increased risk of developing skin malignancies when taking Neoral®.

Cyclosporine, the active ingredient in Neoral®, in recommended dosages, can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporine therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of cyclosporine, and therefore, renal function must be monitored during therapy.

Neoral Description

Neoral® is an oral formulation of cyclosporine that immediately forms a microemulsion in an aqueous environment.

Cyclosporine, the active principle in Neoral®, is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.

Chemically, cyclosporine is designated as [R - [R*,R* - (E)]] - cyclic - (L - alanyl - D - alanyl - N - methyl - L - leucyl - N - methyl - L - leucyl - N - methyl - L - valyl - 3 - hydroxy - N,4 - dimethyl - L - 2 - amino - 6 - octenoyl - L - α -amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).

Neoral® Soft Gelatin Capsules

(cyclosporine capsules, USP) MODIFIED are available in 25 mg and 100 mg strengths. 

Each 25 mg capsule contains:

cyclosporine……………………………………………………………………………...25 mg

alcohol, USP dehydrated……..............................................................11.9% v/v (9.5% wt/vol.)

Each 100 mg capsule contains:

cyclosporine……………………………………………………………………………...100 mg

alcohol, USP dehydrated……...............................................................11.9% v/v (9.5% wt/vol.)

Inactive Ingredients: Corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil NF, DL-α-tocopherol USP, gelatin NF, glycerol, iron oxide black, propylene glycol USP, titanium dioxide USP, carmine, and other ingredients.

Neoral® Oral Solution

(cyclosporine oral solution, USP) MODIFIED is available in 50 mL bottles.

Each mL contains:

cyclosporine…………………………………………………………………………100 mg/mL

alcohol, USP dehydrated......................................................................11.9% v/v (9.5% wt/vol.)

Inactive Ingredients: Corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil NF, DL-α -tocopherol USP, propylene glycol USP.

The chemical structure of cyclosporine (also known as cyclosporin A) is:

     

Neoral - Clinical Pharmacology

Cyclosporine is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund’s adjuvant arthritis, and graft vs. host disease in many animal species for a variety of organs.

The effectiveness of cyclosporine results from specific and reversible inhibition of immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release including interleukin-2.

No effects on phagocytic function (changes in enzyme secretions, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) have been detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man.

Pharmacokinetics

The immunosuppressive activity of cyclosporine is primarily due to parent drug. Following oral administration, absorption of cyclosporine is incomplete. The extent of absorption of cyclosporine is dependent on the individual patient, the patient population, and the formulation. Elimination of cyclosporine is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in urine. The disposition of cyclosporine from blood is generally biphasic, with a terminal half-life of approximately 8.4 hours (range 5-18 hours). Following intravenous administration, the blood clearance of cyclosporine (assay: HPLC) is approximately 5-7 mL/min/kg in adult recipients of renal or liver allografts. Blood cyclosporine clearance appears to be slightly slower in cardiac transplant patients.

The Neoral® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral® Oral Solution (cyclosporine oral solution, USP) MODIFIED are bioequivalent. Neoral® Oral Solution diluted with orange juice or apple juice is bioequivalent to Neoral Oral Solution diluted with water. The effect of milk on the bioavailability of cyclosporine when administered as Neoral Oral Solution has not been evaluated.

The relationship between administered dose and exposure (area under the concentration versus time curve, AUC) is linear within the therapeutic dose range. The intersubject variability (total, %CV) of cyclosporine exposure (AUC) when Neoral® or Sandimmune® is administered ranges from approximately 20% to 50% in renal transplant patients. This intersubject variability contributes to the need for individualization of the dosing regimen for optimal therapy (see DOSAGE AND ADMINISTRATION). Intrasubject variability of AUC in renal transplant recipients (%CV) was 9%-21% for Neoral® and 19%-26% for Sandimmune®. In the same studies, intrasubject variability of trough concentrations (%CV) was 17%-30% for Neoral® and 16%-38% for Sandimmune®.

Absorption

Neoral® has increased bioavailability compared to Sandimmune®. The absolute bioavailability of cyclosporine administered as Sandimmune® is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. The absolute bioavailability of cyclosporine administered as Neoral® has not been determined in adults. In studies of renal transplant, rheumatoid arthritis and psoriasis patients, the mean cyclosporine AUC was approximately 20% to 50% greater and the peak blood cyclosporine concentration (Cmax) was approximately 40% to 106% greater following administration of Neoral® compared to following administration of Sandimmune®. The dose normalized AUC in de novo liver transplant patients administered Neoral® 28 days after transplantation was 50% greater and Cmax was 90% greater than in those patients administered Sandimmune®. AUC and Cmax are also increased (Neoral® relative to Sandimmune®) in heart transplant patients, but data are very limited. Although the AUC and Cmax values are higher on Neoral® relative to Sandimmune®, the pre-dose trough concentrations (dose-normalized) are similar for the two formulations.

Following oral administration of Neoral®, the time to peak blood cyclosporine concentrations (Tmax) ranged from 1.5-2.0 hours. The administration of food with Neoral® decreases the cyclosporine AUC and Cmax. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before Neoral® administration decreased the AUC by 13% and Cmax by 33%. The effects of a low fat meal (667 kcal, 15 grams fat) were similar.

The effect of T-tube diversion of bile on the absorption of cyclosporine from Neoral® was investigated in eleven de novo liver transplant patients. When the patients were administered Neoral® with and without T-tube diversion of bile, very little difference in absorption was observed, as measured by the change in maximal cyclosporine blood concentrations from pre-dose values with the T-tube closed relative to when it was open: 6.9±41% (range -55% to 68%).

Pharmacokinetic Parameters (mean±SD)
Dose/day1 Dose/weight AUC2 Cmax Trough3 CL/F CL/F
Patient Population (mg/d) (mg/kg/d) (ng·hr/mL) (ng/mL) (ng/mL) (mL/min) (mL/min/kg)
De novo renal transplant4 597±174 7.95±2.81 8772±2089 1802±428 361±129 593±204 7.8±2.9
Week 4 (N=37)
Stable renal transplant4 344±122 4.10±1.58 6035±2194 1333±469 251±116 492±140 5.9±2.1
(N=55)
De novo liver transplant5 458±190 6.89±3.68 7187±2816 1555±740 268±101 577±309 8.6±5.7
Week 4 (N=18)
De novo rheumatoid arthritis6 182±55.6 2.37±0.36 2641±877 728±263 96.4±37.7 613±196 8.3±2.8
(N=23)
De novo psoriasis6 189±69.8 2.48±0.65 2324±1048 655±186 74.9±46.7 723±186 10.2±3.9
Week 4 (N=18)

1Total daily dose was divided into two doses administered every 12 hours

2AUC was measured over one dosing interval

3Trough concentration was measured just prior to the morning Neoral® dose, approximately 12 hours after the previous dose

4Assay: TDx specific monoclonal fluorescence polarization immunoassay

5Assay: Cyclo-trac specific monoclonal radioimmunoassay

6Assay: INCSTAR specific monoclonal radioimmunoassay

Distribution

Cyclosporine is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as 3-5 L/kg in solid organ transplant recipients. In blood, the distribution is concentration dependent. Approximately 33%-47% is in plasma, 4%-9% in lymphocytes, 5%-12% in granulocytes, and 41%-58% in erythrocytes. At high concentrations, the binding capacity of leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins. Cyclosporine is excreted in human milk. (See PRECAUTIONS, Nursing Mothers)

Metabolism

Cyclosporine is extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to a lesser degree in the gastrointestinal tract, and the kidney. The metabolism of cyclosporine can be altered by the co-administration of a variety of agents. (See PRECAUTIONS, Drug Interactions) At least 25 metabolites have been identified from human bile, feces, blood, and urine. The biological activity of the metabolites and their contributions to toxicity are considerably less than those of the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. At steady state following the oral administration of Sandimmune®, the mean AUCs for blood concentrations of M1, M9, and M4N are about 70%, 21%, and 7.5% of the AUC for blood cyclosporine concentrations, respectively. Based on blood concentration data from stable renal transplant patients (13 patients administered Neoral® and Sandimmune® in a crossover study), and bile concentration data from de novo liver transplant patients (4 administered Neoral®, 3 administered Sandimmune®), the percentage of dose present as M1, M9, and M4N metabolites is similar when either Neoral® or Sandimmune® is administered.

Excretion

Only 0.1% of a cyclosporine dose is excreted unchanged in the urine. Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Neither dialysis nor renal failure alter cyclosporine clearance significantly.

Drug Interactions

(See PRECAUTIONS, Drug Interactions) When diclofenac or methotrexate was co-administered with cyclosporine in rheumatoid arthritis patients, the AUC of diclofenac and methotrexate, each was significantly increased. (See PRECAUTIONS, Drug Interactions) No clinically significant pharmacokinetic interactions occurred between cyclosporine and aspirin, ketoprofen, piroxicam, or indomethacin.

Special Populations

Pediatric Population

Pharmacokinetic data from pediatric patients administered Neoral® or Sandimmune® are very limited. In 15 renal transplant patients aged 3-16 years, cyclosporine whole blood clearance after IV administration of Sandimmune® was 10.6±3.7 mL/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2-16, the cyclosporine clearance ranged from 9.8-15.5 mL/min/kg. In 9 liver transplant patients aged 0.6-5.6 years, clearance was 9.3±5.4 mL/min/kg (assay: HPLC).

In the pediatric population, Neoral® also demonstrates an increased bioavailability as compared to Sandimmune®. In 7 liver de novo transplant patients aged 1.4-10 years, the absolute bioavailability of Neoral® was 43% (range 30%-68%) and for Sandimmune® in the same individuals absolute bioavailability was 28% (range 17%-42%).

Pediatric Pharmacokinetic Parameters (mean±SD)
Dose/day Dose/weight AUC1 Cmax CL/F CL/F
Patient Population (mg/d) (mg/kg/d) (ng·hr/mL) (ng/mL) (mL/min) (mL/min/kg)
Stable liver transplant2
Age 2-8, Dosed TID (N=9) 101±25 5.95±1.32 2163±801 629±219 285±94 16.6±4.3
Age 8-15, Dosed BID (N=8) 188±55 4.96±2.09 4272±1462 975±281 378±80 10.2±4.0
Stable liver transplant3
Age 3, Dosed BID (N=1) 120 8.33 5832 1050 171 11.9
Age 8-15, Dosed BID (N=5) 158±55 5.51±1.91 4452±2475 1013±635 328±121 11.0±1.9
Stable renal transplant3
Age 7-15, Dosed BID (N=5) 328±83 7.37±4.11 6922±1988 1827±487 418±143 8.7±2.9

     1AUC was measured over one dosing interval
2Assay: Cyclo-trac specific monoclonal radioimmunoassay
3Assay: TDx specific monoclonal fluorescence polarization immunoassay

Geriatric Population

Comparison of single dose data from both normal elderly volunteers (N=18, mean age 69 years) and elderly rheumatoid arthritis patients (N=16, mean age 68 years) to single dose data in young adult volunteers (N=16, mean age 26 years) showed no significant difference in the pharmacokinetic parameters.

Clinical Trials

Rheumatoid Arthritis

The effectiveness of Sandimmune® and Neoral® in the treatment of severe rheumatoid arthritis was evaluated in 5 clinical studies involving a total of 728 cyclosporine treated patients and 273 placebo treated patients.

A summary of the results is presented for the “responder” rates per treatment group, with a responder being defined as a patient having completed the trial with a 20% improvement in the tender and the swollen joint count and a 20% improvement in 2 of 4 of investigator global, patient global, disability, and erythrocyte sedimentation rates (ESR) for the Studies 651 and 652 and 3 of 5 of investigator global, patient global, disability, visual analog pain, and ESR for Studies 2008, 654 and 302.

Study 651 enrolled 264 patients with active rheumatoid arthritis with at least 20 involved joints, who had failed at least one major RA drug, using a 3:3:2 randomization to one of the following three groups: (1) cyclosporine dosed at 2.5-5 mg/kg/day, (2) methotrexate at 7.5-15 mg/week, or (3) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 3.1 mg/kg/day. See Graph below.

Study 652 enrolled 250 patients with active RA with >6 active painful or tender joints who had failed at least one major RA drug. Patients were randomized using a 3:3:2 randomization to 1 of 3 treatment arms: (1) 1.5-5 mg/kg/day of cyclosporine, (2) 2.5-5 mg/kg/day of cyclosporine, and (3) placebo. Treatment duration was 16 weeks. The mean cyclosporine dose for group 2 at the last visit was 2.92 mg/kg/day. See Graph below.

Study 2008 enrolled 144 patients with active RA and >6 active joints who had unsuccessful treatment courses of aspirin and gold or Penicillamine. Patients were randomized to 1 of 2 treatment groups (1) cyclosporine 2.5-5 mg/kg/day with adjustments after the first month to achieve a target trough level and (2) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 3.63 mg/kg/day. See Graph below.

Study 654 enrolled 148 patients who remained with active joint counts of 6 or more despite treatment with maximally tolerated methotrexate doses for at least three months. Patients continued to take their current dose of methotrexate and were randomized to receive, in addition, one of the following medications: (1) cyclosporine 2.5 mg/kg/day with dose increases of 0.5 mg/kg/day at weeks 2 and 4 if there was no evidence of toxicity and further increases of 0.5 mg/kg/day at weeks 8 and 16 if a <30% decrease in active joint count occurred without any significant toxicity; dose decreases could be made at any time for toxicity or (2) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 2.8 mg/kg/day (range: 1.3-4.1). See Graph below.

Study 302 enrolled 299 patients with severe active RA, 99% of whom were unresponsive or intolerant to at least one prior major RA drug. Patients were randomized to 1 of 2 treatment groups (1) Neoral® and (2) cyclosporine, both of which were started at 2.5 mg/kg/day and increased after 4 weeks for inefficacy in increments of 0.5 mg/kg/day to a maximum of 5 mg/kg/day and decreased at any time for toxicity. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 2.91 mg/kg/day (range: 0.72-5.17) for Neoral® and 3.27 mg/kg/day (range: 0.73-5.68) for cyclosporine. See Graph below.

Indications and Usage for Neoral

Kidney, Liver, and Heart Transplantation

Neoral® is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Neoral® has been used in combination with azathioprine and corticosteroids.

Rheumatoid Arthritis

Neoral® is indicated for the treatment of patients with severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate. Neoral® can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone.

Psoriasis

Neoral® is indicated for the treatment of adult, nonimmunocompromised patients with severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (eg., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated.

While rebound rarely occurs, most patients will experience relapse with Neoral® as with other therapies upon cessation of treatment.

Contraindications

General

Neoral® is contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.

Rheumatoid Arthritis

Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive Neoral®.

Psoriasis

Psoriasis patients who are treated with Neoral® should not receive concomitant PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar or radiation therapy. Psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive Neoral®.

Warnings

(See also Boxed WARNING)

All Patients

Cyclosporine, the active ingredient of Neoral®, can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of cyclosporine. Renal dysfunction including structural kidney damage is a potential consequence of Neoral® and therefore renal function must be monitored during therapy. Care should be taken in using cyclosporine with nephrotoxic drugs. (See PRECAUTIONS) 

Patients receiving Neoral® require frequent monitoring of serum creatinine. (See Special Monitoring under DOSAGE AND ADMINISTRATION) Elderly patients should be monitored with particular care, since decreases in renal function also occur with age. If patients are not properly monitored and doses are not properly adjusted, cyclosporine therapy can be associated with the occurrence of structural kidney damage and persistent renal dysfunction.

An increase in serum creatinine and BUN may occur during Neoral® therapy and reflect a reduction in the glomerular filtration rate. Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated. The frequency and severity of serum creatinine elevations increase with dose and duration of cyclosporine therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation.

Because Neoral® is not bioequivalent to Sandimmune®, conversion from Neoral® to Sandimmune® using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations. Conversion from Neoral® to Sandimmune® should be made with increased monitoring to avoid the potential of underdosing.

Kidney, Liver, and Heart Transplant

Cyclosporine, the active ingredient of Neoral®, can cause nephrotoxicity and hepatotoxicity when used in high doses. It is not unusual for serum creatinine and BUN levels to be elevated during cyclosporine therapy. These elevations in renal transplant patients do not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated.

Based on the historical Sandimmune® experience with oral solution, nephrotoxicity associated with cyclosporine had been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation. Mild nephrotoxicity was generally noted 2-3 months after renal transplant and consisted of an arrest in the fall of the pre-operative elevations of BUN and creatinine at a range of 35-45 mg/dl and 2.0-2.5 mg/dl respectively. These elevations were often responsive to cyclosporine dosage reduction.

More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine. Since these events are similar to renal rejection episodes, care must be taken to differentiate between them. This form of nephrotoxicity is usually responsive to cyclosporine dosage reduction.

Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated with one or the other. It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection.


Nephrotoxicity vs. Rejection
Parameter Nephrotoxicity Rejection
History Donor >50 years old or hypotensive
Prolonged kidney preservation
Prolonged anastomosis time
Concomitant nephrotoxic drugs
Anti-donor immune response
Retransplant patient
Clinical Often >6 weeks postopb
Prolonged initial nonfunction (acute tubular necrosis)
Often < 4 weeks postopb
Fever > 37.5°C
Weight gain > 0.5 kg
Graft swelling and tenderness
Decrease in daily urine volume > 500 mL (or 50%)
Laboratory CyA serum trough level > 200 ng/mL
Gradual rise in Cr (< 0.15 mg/dl/day)a
Cr plateau < 25% above baseline
BUN/Cr ≥ 20
CyA serum trough level < 150 ng/mL
Rapid rise in Cr (> 0.3 mg/dl/day) a
Cr > 25% above baseline
BUN/Cr < 20
Biopsy Arteriolopathy (medial hypertrophy a, hyalinosis,
nodular deposits, intimal thickening, endothelial
vacuolization, progressive scarring)
Tubular atrophy, isometric vacuolization, isolated calcifications
Minimal edema
Mild focal infiltratesc

Diffuse interstitial fibrosis, often striped form
Endovasculitisc (proliferationa, intimal arteritisb,
necrosis, sclerosis)

Tubulitis with RBCb and WBCb casts, some irregular vacuolization
Interstitial edemac and hemorrhageb
Diffuse moderate to severe mononuclear infiltratesd
Glomerulitis (mononuclear cells)c
Aspiration Cytology CyA deposits in tubular and endothelial cells
Fine isometric vacuolization of tubular cells
Inflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid cells, and activated T-cells
These strongly express HLA-DR antigens
Urine Cytology Tubular cells with vacuolization and granularization Degenerative tubular cells, plasma cells, and lymphocyturia > 20% of sediment
Manometry Ultrasonography Intracapsular pressure < 40 mm Hgb
Unchanged graft cross sectional area
Intracapsular pressure > 40 mm Hgb
Increase in graft cross sectional area
AP diameter ≥ Transverse diameter
Magnetic Resonance Imagery Normal appearance Loss of distinct corticomedullary junction, swelling image intensity of parachyma approaching that of psoas, loss of hilar fat
Radionuclide Scan Normal or generally decreased perfusion
Decrease in tubular function
(131 I-hippuran) > decrease in perfusion (99m Tc DTPA)
Patchy arterial flow
Decrease in perfusion > decrease in tubular function
Increased uptake of Indium 111 labeled platelets or Tc-99m in colloid
Therapy Responds to decreased cyclosporine Responds to increased steroids or antilymphocyte globulin

ap < 0.05, bp < 0.01, cp < 0.001, dp < 0.0001

A form of a cyclosporine-associated nephropathy is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5%-15% of transplant recipients who have received cyclosporine will fail to show a reduction in rising serum creatinine despite a decrease or discontinuation of cyclosporine therapy. Renal biopsies from these patients will demonstrate one or several of the following alterations: tubular vacuolization, tubular microcalcifications, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy. Though none of these morphologic changes is entirely specific, a diagnosis of cyclosporine-associated structural nephrotoxicity requires evidence of these findings.

When considering the development of cyclosporine-associated nephropathy, it is noteworthy that several authors have reported an association between the appearance of interstitial fibrosis and higher cumulative doses or persistently high circulating trough levels of cyclosporine. This is particularly true during the first 6 post-transplant months when the dosage tends to be highest and when, in kidney recipients, the organ appears to be most vulnerable to the toxic effects of cyclosporine. Among other contributing factors to the development of interstitial fibrosis in these patients are prolonged perfusion time, warm ischemia time, as well as episodes of acute toxicity, and acute and chronic rejection. The reversibility of interstitial fibrosis and its correlation to renal function have not yet been determined. Reversibility of arteriolopathy has been reported after stopping cyclosporine or lowering the dosage.

Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated.

In the event of severe and unremitting rejection, when rescue therapy with pulse steroids and monoclonal antibodies fail to reverse the rejection episode, it may be preferable to switch to alternative immunosuppressive therapy rather than increase the Neoral® dose to excessive levels.

Occasionally patients have developed a syndrome of thrombocytopenia and microangiopathic hemolytic anemia which may result in graft failure. The vasculopathy can occur in the absence of rejection and is accompanied by avid platelet consumption within the graft as demonstrated by Indium 111 labeled platelet studies. Neither the pathogenesis nor the management of this syndrome is clear. Though resolution has occurred after reduction or discontinuation of cyclosporine and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans. (See ADVERSE REACTIONS)

Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.

Hepatotoxicity associated with cyclosporine use had been noted in 4% of cases of renal transplantation, 7% of cases of cardiac transplantation, and 4% of cases of liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine were used and consisted of elevations of hepatic enzymes and bilirubin. The chemistry elevations usually decreased with a reduction in dosage.

As in patients receiving other immunosuppressants, those patients receiving cyclosporine are at increased risk for development of lymphomas and other malignancies, particularly those of the skin. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. Because of the danger of oversuppression of the immune system resulting in increased risk of infection or malignancy, a treatment regimen containing multiple immunosuppressants should be used with caution.

There have been reports of convulsions in adult and pediatric patients receiving cyclosporine, particularly in combination with high dose methylprednisolone.

Encephalopathy has been described both in post-marketing reports and in the literature. Manifestations include impaired consciousness, convulsions, visual disturbances (including blindness), loss of motor function, movement disorders and psychiatric disturbances. In many cases, changes in the white matter have been detected using imaging techniques and pathologic specimens. Predisposing factors such as hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood concentrations, and graft-versus-host disease have been noted in many but not all of the reported cases. The changes in most cases have been reversible upon discontinuation of cyclosporine, and in some cases improvement was noted after reduction of dose. It appears that patients receiving liver transplant are more susceptible to encephalopathy than those receiving kidney transplant. Another rare manifestation of cyclosporine-induced neurotoxicity, occurring in transplant patients more frequently than in other indications, is optic disc edema including papilloedema, with possible visual impairment, secondary to benign intracranial hypertension.

Care should be taken in using cyclosporine with nephrotoxic drugs. (See PRECAUTIONS)

Rheumatoid Arthritis

Cyclosporine nephropathy was detected in renal biopsies of 6 out of 60 (10%) rheumatoid arthritis patients after the average treatment duration of 19 months. Only one patient, out of these 6 patients, was treated with a dose ≤4 mg/kg/day. Serum creatinine improved in all but one patient after discontinuation of cyclosporine. The “maximal creatinine increase” appears to be a factor in predicting cyclosporine nephropathy.

There is a potential, as with other immunosuppressive agents, for an increase in the occurrence of malignant lymphomas with cyclosporine. It is not clear whether the risk with cyclosporine is greater than that in rheumatoid arthritis patients or in rheumatoid arthritis patients on cytotoxic treatment for this indication. Five cases of lymphoma were detected: four in a survey of approximately 2,300 patients treated with cyclosporine for rheumatoid arthritis, and another case of lymphoma was reported in a clinical trial. Although other tumors (12 skin cancers, 24 solid tumors of diverse types, and 1 multiple myeloma) were also reported in this survey, epidemiologic analyses did not support a relationship to cyclosporine other than for malignant lymphomas.

Patients should be thoroughly evaluated before and during Neoral® treatment for the development of malignancies. Moreover, use of Neoral® therapy with other immunosuppressive agents may induce an excessive immunosuppression which is known to increase the risk of malignancy.

Psoriasis

(See also Boxed WARNINGS for Psoriasis)

Since cyclosporine is a potent immunosuppressive agent with a number of potentially serious side effects, the risks and benefits of using Neoral® should be considered before treatment of patients with psoriasis. Cyclosporine, the active ingredient in Neoral®, can cause nephrotoxicity and hypertension (see PRECAUTIONS) and the risk increases with increasing dose and duration of therapy. Patients who may be at increased risk such as those with abnormal renal function, uncontrolled hypertension or malignancies, should not receive Neoral®.

Renal dysfunction is a potential consequence of Neoral® therefore renal function must be monitored during therapy.

Patients receiving Neoral® require frequent monitoring of serum creatinine. (See Special Monitoring under DOSAGE AND ADMINISTRATION) Elderly patients should be monitored with particular care, since decreases in renal function also occur with age. If patients are not properly monitored and doses are not properly adjusted, cyclosporine therapy can cause structural kidney damage and persistent renal dysfunction.

An increase in serum creatinine and BUN may occur during Neoral® therapy and reflects a reduction in the glomerular filtration rate.

Kidney biopsies from 86 psoriasis patients treated for a mean duration of 23 months with 1.2-7.6 mg/kg/day of cyclosporine showed evidence of cyclosporine nephropathy in 18/86 (21%) of the patients. The pathology consisted of renal tubular atrophy and interstitial fibrosis. On repeat biopsy of 13 of these patients maintained on various dosages of cyclosporine for a mean of 2 additional years, the number with cyclosporine induced nephropathy rose to 26/86 (30%). The majority of patients (19/26) were on a dose of ≥5.0 mg/kg/day (the highest recommended dose is 4 mg/kg/day). The patients were also on cyclosporine for greater than 15 months (18/26) and/or had a clinically significant increase in serum creatinine for greater than 1 month (21/26). Creatinine levels returned to normal range in 7 of 11 patients in whom cyclosporine therapy was di

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