Cyclosporine ORAL SOLUTION USP MODIFIED
WARNING
Only physicians experienced in management of systemic immunosuppressive therapy for the indicated disease should prescribe Cyclosporine Oral Solution USP MODIFIED. At doses used in solid organ transplantation, only physicians experienced in immunosuppressive therapy and management of organ transplant recipients should prescribe Cyclosporine Oral Solution USP MODIFIED. 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.
Cyclosporine Oral Solution USP MODIFIED, a systemic immunosuppressant, may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients Cyclosporine Oral Solution USP MODIFIED 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.
Cyclosporine Oral Solution USP MODIFIED has increased bioavailability in comparison to Sandimmune® (Cyclosporine Oral Solution USP). Cyclosporine Oral Solution USP MODIFIED and Sandimmune® (Cyclosporine Oral Solution USP) are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, Cyclosporine exposure will be greater with Cyclosporine Oral Solution USP MODIFIED than with Sandimmune® (Cyclosporine Oral Solution USP). If a patient who is receiving exceptionally high doses of Sandimmune® (Cyclosporine Oral Solution USP) is converted to Cyclosporine Oral Solution USP MODIFIED, particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking Cyclosporine Oral Solution USP MODIFIED 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 Cyclosporine Oral Solution USP MODIFIED.
Cyclosporine, the active ingredient in Cyclosporine Oral Solution USP MODIFIED, 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.
Cyclosporine Description
Cyclosporine Oral Solution USP MODIFIED is an oral formulation of Cyclosporine that immediately forms an emulsion in an aqueous environment.
Cyclosporine, the active principle in Cyclosporine Oral Solution USP MODIFIED, is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Mycelium sterilae.
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) and has the following structural formula:
Each mL of Cyclosporine Oral Solution USP MODIFIED contains 100 mg/mL Cyclosporine and 15.3% v/v (12.18% wt/vol) dehydrated alcohol and has the following inactive ingredients: polyoxyl 40 hydrogenated castor oil, polyglycerol (3) oleate and polyglycerol (10) oleate.
Cyclosporine - 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 to 18 hours). Following intravenous administration, the blood clearance of Cyclosporine (assay: HPLC) is approximately 5 to 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 Cyclosporine Capsules USP MODIFIED and Cyclosporine Oral Solution USP MODIFIED are bioequivalent. Cyclosporine Oral Solution USP MODIFIED diluted with orange juice or apple juice is bioequivalent to Cyclosporine Oral Solution USP MODIFIED diluted with water. The effect of milk on the bioavailability of Cyclosporine when administered as Cyclosporine Oral Solution USP MODIFIED 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 Cyclosporine Oral Solution USP MODIFIED or Sandimmune® (Cyclosporine Oral Solution USP) 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% to 21% for Cyclosporine Oral Solution USP MODIFIED and 19% to 26% for Sandimmune® (Cyclosporine Oral Solution USP). In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for Cyclosporine Oral Solution USP MODIFIED and 16% to 38% for Sandimmune® (Cyclosporine Oral Solution USP).
Absorption
Cyclosporine Oral Solution USP MODIFIED has increased bioavailability compared to Sandimmune® (Cyclosporine Oral Solution USP). The absolute bioavailability of Cyclosporine administered as Sandimmune® (Cyclosporine Oral Solution USP) 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 Cyclosporine Oral Solution USP MODIFIED 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 Cyclosporine Oral Solution USP MODIFIED compared to following administration of Sandimmune® (Cyclosporine Oral Solution USP). The dose normalized AUC in de novo liver transplant patients administered Cyclosporine Oral Solution USP MODIFIED 28 days after transplantation was 50% greater and Cmax was 90% greater than in those patients administered Sandimmune® (Cyclosporine Oral Solution USP). AUC and Cmax are also increased (Cyclosporine Oral Solution USP MODIFIED relative to Sandimmune® (Cyclosporine Oral Solution USP)) in heart transplant patients, but data are very limited. Although the AUC and Cmax values are higher on Cyclosporine Oral Solution USP MODIFIED relative to Sandimmune® (Cyclosporine Oral Solution USP), the pre-dose trough concentrations (dose-normalized) are similar for the two formulations.
Following oral administration of Cyclosporine Oral Solution USP MODIFIED, the time to peak blood Cyclosporine concentrations (Tmax) ranged from 1.5 to 2 hours. The administration of food with Cyclosporine Oral Solution USP MODIFIED decreases the Cyclosporine AUC and Cmax. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before Cyclosporine Oral Solution USP MODIFIED 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 Cyclosporine Oral Solution USP MODIFIED was investigated in eleven de novo liver transplant patients. When the patients were administered Cyclosporine Oral Solution USP MODIFIED 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%).
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| Patient Population | Dose/day1*(mg/d) | Dose/weight (mg/kg/d) | AUC2† (ng•hr/mL) | Cmax(ng/mL) | Trough3‡ (ng/mL) | CL/F (mL/min) | CL/F (mL/min/kg) |
| De novo renal transplant4§ Week 4 (N = 37) | 597 ± 174 | 7.95 ± 2.81 | 8772 ± 2089 | 1802 ± 428 | 361 ± 129 | 593 ± 204 | 7.8 ± 2.9 |
| Stable renal transplant4§ (N = 55) | 344 ± 122 | 4.10 ± 1.58 | 6035 ± 2194 | 1333 ± 469 | 251 ± 116 | 492 ± 140 | 5.9 ± 2.1 |
| De novo liver transplant5¶Week 4 (N = 18) | 458 ± 190 | 6.89 ± 3.68 | 7187 ± 2816 | 1555 ± 740 | 268 ± 101 | 577 ± 309 | 8.6 ± 5.7 |
| De novo rheumatoid arthritis6# (N = 23) | 182 ± 55.6 | 2.37 ± 0.36 | 2641 ± 877 | 728 ± 263 | 96.4 ± 37.7 | 613 ± 196 | 8.3 ± 2.8 |
| De novo psoriasis6# Week 4 (N = 18) | 189 ± 69.8 | 2.48 ± 0.65 | 2324 ± 1048 | 655 ± 186 | 74.9 ± 46.7 | 723 ± 186 | 10.2 ± 3.9 |
Distribution
Cyclosporine is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as 3 to 5 L/kg in solid organ transplant recipients. In blood, the distribution is concentration dependent. Approximately 33% to 47% is in plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 41% to 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 coadministration 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® (Cyclosporine Oral Solution USP), 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 Cyclosporine Oral Solution USP MODIFIED and Sandimmune® (Cyclosporine Oral Solution USP) in a crossover study], and bile concentration data from de novo liver transplant patients (4 administered Cyclosporine Oral Solution USP MODIFIED; 3 administered Sandimmune® (Cyclosporine Oral Solution USP)), the percentage of dose present as M1, M9 and M4N metabolites is similar when either Cyclosporine Oral Solution USP MODIFIED or Sandimmune® (Cyclosporine Oral Solution USP) 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 coadministered 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 Cyclosporine Oral Solution USP MODIFIED or Sandimmune® (Cyclosporine Oral Solution USP) are very limited. In 15 renal transplant patients aged 3 to 16 years, Cyclosporine whole blood clearance after IV administration of Sandimmune® (Cyclosporine Oral Solution USP) was 10.6 ± 3.7 mL/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2 to 16, the Cyclosporine clearance ranged from 9.8 to 15.5 mL/min/kg. In 9 liver transplant patients aged 0.6 to 5.6 years, clearance was 9.3 ± 5.4 mL/min/kg (assay: HPLC).
In the pediatric population, Cyclosporine Oral Solution USP MODIFIED also demonstrates an increased bioavailability as compared to Sandimmune® (Cyclosporine Oral Solution USP). In 7 liver de novo transplant patients aged 1.4 to 10 years, the absolute bioavailability of Cyclosporine Oral Solution USP MODIFIED was 43% (range 30% to 68%) and for Sandimmune® (Cyclosporine Oral Solution USP) in the same individuals absolute bioavailability was 28% (range 17% to 42%).
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Patient Population | Dose/day (mg/d) | Dose/weight (mg/kg/d) | AUC1*(ng•hr/mL) | Cmax (ng/mL) | CL/F (mL/min) | CL/F (mL/min/kg) |
| Stable liver transplant2† Age 2 to 8, dosed TID (N = 9) Age 8 to 15, dosed BID (N = 8) | 101 ± 25 188 ± 55 | 5.95 ± 1.32 4.96 ± 2.09 | 2163 ± 801 4272 ± 1462 | 629 ± 219 975 ± 281 | 285 ± 94 378 ± 80 | 16.6 ± 4.3 10.2 ± 4.0 |
| Stable liver transplant3‡ Age 3, dosed BID (N = 1) Age 8 to 15, dosed BID (N = 5) | 120 158 ± 55 | 8.33 5.51 ± 1.91 | 5832 4452 ± 2475 | 1050 1013 ± 635 | 171 328 ± 121 | 11.9 11.0 ± 1.9 |
Stable renal transplant3‡ Age 7 to 15, dosed BID (N = 5) | 328 ± 83 | 7.37 ± 4.11 | 6922 ± 1988 | 1827 ± 487 | 418 ± 143 | 8.7 ± 2.9 |
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® (Cyclosporine Oral Solution USP) and Cyclosporine Oral Solution USP MODIFIED 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 to 5 mg/kg/day, (2) methotrexate at 7.5 to 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 to 5 mg/kg/day of Cyclosporine, (2) 2.5 to 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 to 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 to 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) Cyclosporine Oral Solution USP MODIFIED 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 to 5.17) for Cyclosporine Oral Solution USP MODIFIED and 3.27 mg/kg/day (range: 0.73 to 5.68) for Cyclosporine. See graph below.
Indications and Usage for Cyclosporine
Kidney, Liver, and Heart Transplantation
Cyclosporine Oral Solution USP MODIFIED is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine Oral Solution USP MODIFIED has been used in combination with azathioprine and corticosteroids.
Rheumatoid Arthritis
Cyclosporine Oral Solution USP MODIFIED is indicated for the treatment of patients with severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate. Cyclosporine Oral Solution USP MODIFIED can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone.
Psoriasis
Cyclosporine Oral Solution USP MODIFIED 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 (e.g., 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 Cyclosporine Oral Solution USP MODIFIED as with other therapies upon cessation of treatment.
Contraindications
General
Cyclosporine Oral Solution USP MODIFIED 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 Cyclosporine Oral Solution USP MODIFIED.
Psoriasis
Psoriasis patients who are treated with Cyclosporine Oral Solution USP MODIFIED 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 Cyclosporine Oral Solution USP MODIFIED.
Warnings
(See also Boxed WARNING)
All Patients
Cyclosporine, the active ingredient of Cyclosporine Oral Solution USP MODIFIED, can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of Cyclosporine. Renal dysfunction including structural kidney damage is a potential consequence of Cyclosporine Oral Solution USP MODIFIED and therefore renal function must be monitored during therapy. Care should be taken in using Cyclosporine with nephrotoxic drugs (see PRECAUTIONS).
Patients receiving Cyclosporine Oral Solution USP MODIFIED require frequent monitoring of serum creatinine (see DOSAGE AND ADMINISTRATION, Special Monitoring). 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 Cyclosporine Oral Solution USP MODIFIED 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 Cyclosporine Oral Solution USP MODIFIED is not bioequivalent to Sandimmune® (Cyclosporine Oral Solution USP), conversion from Cyclosporine Oral Solution USP MODIFIED to Sandimmune® (Cyclosporine Oral Solution USP) using a 1:1 ratio (mg/kg/day) may result in lower Cyclosporine blood concentrations. Conversion from Cyclosporine Oral Solution USP MODIFIED to Sandimmune® (Cyclosporine Oral Solution USP) should be made with increased monitoring to avoid the potential of underdosing.
Kidney, Liver, and Heart Transplant
Cyclosporine, the active ingredient of Cyclosporine Oral Solution USP MODIFIED, 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® (Cyclosporine Oral Solution USP) 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 to 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 to 45 mg/dL and 2 to 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.
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| 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 hypertrophyaa†, 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 | Intracapsular pressure <40 mm Hgb* | Intracapsular pressure >40 mm Hgb* |
| Ultrasonography | Unchanged graft cross sectional area | 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 ( 131I-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 |
A form of a Cyclosporine-associated nephropathy is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5% to 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 Cyclosporine Oral Solution USP MODIFIED 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. Patients taking Cyclosporine should be warned to avoid excess ultraviolet light exposure. 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. Some malignancies may be fatal. Transplant patients receiving Cyclosporine are at increased risk for serious infection with fatal outcome.
Latent Viral Infections
Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus-associated nephropathy which has been observed in patients receiving immunosuppressants, including Cyclosporine Oral Solution USP MODIFIED. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss. Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy.
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 postmarketing 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 Cyclosporine Oral Solution USP MODIFIED treatment for the development of malignancies. Moreover, use of Cyclosporine Oral Solution USP MODIFIED 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 Cyclosporine Oral Solution USP MODIFIED should be considered before treatment of patients with psoriasis. Cyclosporine, the active ingredient in Cyclosporine Oral Solution USP MODIFIED, can cause nephrotoxicity and hypertension (see PRECAUTIONS) and the risk increases with incr
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