Cyclosporine - Warnings and Precautions

WARNINGS (See also BOXED WARNING ) All Patients Cyclosporine, the active ingredient of cyclosporine capsules, (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 capsules (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 capsules (modified) 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 cyclosporine capsules (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 capsules (modified) is not bioequivalent to Sandimmune ® , conversion from cyclosporine capsules (modified) to Sandimmune ® using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations.

Conversion from cyclosporine capsules (modified) to Sandimmune ® should be made with increased monitoring to avoid the potential of underdosing.

Kidney, Liver, and Heart Transplant Nephrotoxicity Cyclosporine, the active ingredient of cyclosporine capsules, (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 ® 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 2.0 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.

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 postop b Prolonged initial nonfunction (acute tubular necrosis) Often < 4 weeks postop b 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 infiltrates c Endovasculitis c (proliferation a , intimal arteritis b , necrosis, sclerosis) Tubulitis with RBC b and WBC b casts, some irregular vacuolization Interstitial edema c and hemorrhage b Diffuse moderate to severe mononuclear infiltrates d Aspiration Cytology Diffuse interstitial fibrosis, often striped form CyA deposits in tubular and endothelial cells Fine isometric vacuolization of tubular cells Glomerulitis (mononuclear cells) c 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 Hg b Unchanged graft cross sectional area Intracapsular pressure > 40 mm Hg b 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 a p < 0.05, b p < 0.01, c p < 0.001, d p < 0.0001 A form of a cyclosporine-associated nephropathy is characterized by serial deterioration in renal function and morphologic changes in the kidneys.