Cyclosporine Prescribing Information
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 [MODIFIED].
Cyclosporine, the active ingredient in cyclosporine capsules [MODIFIED] and cyclosporine oral solution [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 capsules, USP [MODIFIED] and cyclosporine oral solution, USP [MODIFIED] are indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine capsules, USP [MODIFIED] and cyclosporine oral solution, USP [MODIFIED] have been used in combination with azathioprine and corticosteroids.
The daily dose of cyclosporine [MODIFIED] should always be given in two divided doses (b.i.d.). It is recommended that cyclosporine [MODIFIED] be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided.
Cyclosporine [MODIFIED] is contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.
The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.
All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant use of nonsteroidal anti-inflammatory drugs with cyclosporine, particularly in the setting of dehydration, may potentiate renal dysfunction. Caution should be exercised when using other drugs which are known to impair renal function. (
Cyclosporine, the active ingredient of cyclosporine [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 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.
| 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 postopp < 0.01, Prolonged initial nonfunction (acute tubular necrosis) | Often <4 weeks postop 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)p < 0.05, Cr plateau <25% above baseline BUN/Cr ≥20 | CyA serum trough level <150 ng/mL Rapid rise in Cr (>0.3 mg/dL/day) Cr >25% above baseline BUN/Cr <20 |
| Biopsy | Arteriolopathy (medial hypertrophy, hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, vacuolization, progressive scarring) | Endovasculitis(proliferation, intimalarteritis, necrosis, sclerosis) |
| Tubular atrophy, isometric vacuolization, isolated calcifications Minimal edema Mild focal infiltratesp < 0.001, | Tubulitis with RBCand WBCcasts, some irregular vacuolization Interstitial edemaand hemorrhage Diffuse moderate to severe mononuclear infiltratesp < 0.0001Glomerulitis (mononuclear cells) | |
| Diffuse interstitial fibrosis, often striped form | ||
| 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 Hg | Intracapsular pressure >40 mm Hg |
| 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 (99mTc 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 concentrations 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 [MODIFIED] dose to excessive blood concentrations.
Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering cyclosporine with other drugs that may impair renal function.