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Basic Drug Info
Drug Name:Cyclosporine
Manufacturer:Morton Grove Pharmaceuticals, Inc.
Other Info:

Rx OnlyProduct No.: 8140Manufactured By: Morton Grove Pharmaceuticals, Inc.                                Morton Grove, IL 6005328140REV.

08-06



Clinical Trials:


Indications and Usage

Cyclosporine is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants.

It is always to be used with adrenal corticosteroids.

The drug may also be used in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents.Because of the risk of anaphylaxis, cyclosporine injection, USP should be reserved for patients who are unable to take the soft gelatin capsules or oral solution.
Contraindications
Cyclosporine oral solution is contraindicated in patients with a hypersensitivity to cyclosporine or any of the ingredients in the formulation.
Hypersensitivity -- Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.

Warnings

(See boxed WARNINGs): Cyclosporine, when used in high doses, can cause hepatotoxicity and nephrotoxicity.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.Nephrotoxicity has 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 transplant and consisted of an arrest in the fall of the preoperative 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 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 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 to one or the other.

It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection. Nephrotoxicity vs Rejection ParameterNephrotoxicityRejection HistoryDonor > 50 years old or hypotensiveProlonged kidney preservationProlonged anastomosis timeConcomitant nephrotoxic drugsAntidonor immune responseRetransplant patient ClinicalOften > 6 weeks postopp < 0.01Prolonged initial nonfunction(acute tubular necrosis)Often < 4 weeks postopFever > 37.5°CWeight gain > 0.5 kgGraft swelling and tendernessDecrease in daily urine volume > 500 mL (or 50%) LaboratoryCyA serum trough level > 200 ng/mLGradual rise in Cr ( < 0.15 mg/dL/day)p < 0.05Cr plateau < 25% above baselineBUN/Cr ? 20CyA serum trough level <150 ng/mLRapid rise in Cr ( > 0.3 mg/dL/day)Cr > 25% above baselineBUN/Cr < 20 BiopsyArteriolopathy (medial hypertrophy, hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, progressive scarring)Endovasculitis (proliferation , intimal arteritis, necrosis, sclerosis) Tubular atrophy, isometric vacuolization, isolated calcificationsTubulitis with RBC and WBC casts, some irregular vacuolization Minimal edemaInterstitial edema and hemorrhage Mild focal infiltratesp < 0.001Diffuse moderate to severe mononuclear infiltratesp < 0.0001 Diffuse interstitial fibrosis, often striped formGlomerulitis (mononuclear cells) Aspiration CytologyCyA deposits in tubular and endothelial cellsFine isometric vacuolization of tubular cellsInflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid cells, and activated T-cellsThese strongly express HLA-DR antigens Urine CytologyTubular cells with vacuolization and granularizationDegenerative tubular cells, plasma cells, and lymphocyturia > 20% of sediment ManometryIntracapsular pressure < 40 mm HgIntracapsular pressure > 40 mm Hg Ultra-sonographyUnchanged graft cross-sectional areaIncrease in graft cross-sectional areaAP diameter ? Transverse diameter Magnetic Resonance ImageryNormal appearanceLoss of distinct corticomedullary junction, swelling, image intensity of parachyma approaching that of psoas, loss of hilar fat Radionuclide ScanNormal or generally decreased perfusionDecrease in tubular function(131 I-hippuran) > decrease in perfusionPatchy arterial flowDecrease in perfusion > decrease in tubular function (99m Tc DTPA)Increased uptake of Indium 111 labeled platelets or Tc-99m in colloid TherapyResponds to decreased cyclosporineResponds to increased steroids or antilymphocyte globulin A form of chronic progressive cyclosporine-associated nephrotoxicity is characterized by serial deterioration in renal function and morphologic changes in the kidneys.

From 5%–15% of transplant recipients will fail to show a reduction in a rising serum creatinine despite a decrease or discontinuation of cyclosporine therapy.

Renal biopsies from these patients will demonstrate an interstitial fibrosis with tubular atrophy.

In addition, toxic tubulopathy, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy may be present.

Though none of these morphologic changes is entirely specific, a histologic diagnosis of chronic progressive cyclosporine-associated nephrotoxicity requires evidence of these.When considering the development of chronic nephrotoxicity 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 posttransplant 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 must be included, 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.Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated.

In patients with persistent high elevations of BUN and creatinine who are unresponsive to dosage adjustments, consideration should be given to switching to other immunosuppressive therapy.

In the event of severe and unremitting rejection, it is preferable to allow the kidney transplant to be rejected and removed rather than increase the cyclosporine dosage to a very high level in an attempt to reverse the rejection.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 has 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, which can also increase susceptibility to infection, cyclosporine should not be administered with other immunosuppressive agents except adrenal corticosteroids.

The efficacy and safety of cyclosporine in combination with other immunosuppressive agents have not been determined.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 patients receiving kidney transplant.Another rare manifestation of cyclosporine-induced neurotoxicity is optic disc edema including papilloedema, with possible visual impairment, secondary to benign intracranial hypertension.Anaphylactic reactions have not been reported with the oral solution which lacks polyoxyethylated castor oil.

In fact, patients experiencing anaphylactic reactions have been treated subsequently with the oral solution without incident.Care should be taken in using cyclosporine with nephrotoxic drugs.

(See PRECAUTIONS)Because cyclosporine is not bioequivalent to Neoral®*(cyclosporine [MODIFIED]), conversion from Neoral®* (cyclosporine [MODIFIED]) to cyclosporine using a 1:1 ratio (mg/kg/day) may result in a lower cyclosporine blood concentration.

Conversion from Neoral®* (cyclosporine [MODIFIED]) to cyclosporine should be made with increased blood concentration monitoring to avoid the potential of underdosing.
Branded Drugs
The following US Branded drugs contain Cyclosporine


GENGRAF -- ABBOTT LABORATORIES

NEORAL -- NOVARTIS PHARMACEUTICALS CORP

SANDIMMUNE -- NOVARTIS PHARMACEUTICALS CORP

RESTASIS -- ALLERGAN INC


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