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Basic Drug Info
Drug Name:Cyclosporine
Manufacturer:Bedford Laboratories
Other Info:

Several study centers have found blood level monitoring of cyclosporine useful in patient management.

While no fixed relationships have yet been established, in one series of 375 consecutive cadaveric renal transplant recipients, dosage was adjusted to achieve specific whole blood 24-hour trough levels of 100 to 200 ng/mL as determined by high-pressure liquid chromatography (HPLC).Of major importance to blood level analysis is the type of assay used.

The above levels are specific to the parent cyclosporine molecule and correlate directly to the new monoclonal specific radioimmunoassays (mRIA-sp).

Nonspecific assays are also available which detect the parent compound molecule and various of its metabolites.

Older studies often cited levels using a nonspecific assay which were roughly twice those of specific assays.

Assay results are not interchangeable and their use should be guided by their approved labeling.

If plasma specimens are employed, levels will vary with the temperature at the time of separation from whole blood.

Plasma levels may range from 1/2 to 1/5 of whole blood levels.

Refer to individual assay labeling for complete instructions.

In addition, Transplantation Proceedings (June 1990) contains position papers and a broad consensus generated at the Cyclosporine-Therapeutic Drug Monitoring conference that year.

Blood level monitoring is not a replacement for renal function monitoring or tissue biopsies.



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 should be reserved for patients who are unable to take the soft gelatin capsules or oral solution.
Contraindications
Cyclosporine is contraindicated in patients with a hypersensitivity to cyclosporine and/or polyoxyethylated castor oil.
Hypersensitivity -- Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.

Warnings

(See boxed WARNING.)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 to 3 months after transplant and consisted of an arrest in the fall of the preoperative elevation 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 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 postopbProlonged initial nonfunction (acute tubular necrosisOften < 4 weeks postopbFever > 37.5°CWeight gain > 0.5 kgGraft swelling and tendernessDecrease in daily urine volume > 500 mL (or 50%) LaboratoryCyA serum trough level > 200 ng/mL Gradual rise in Cr (<0.15 mg/dL/day)aCr plateau < 25% above baseline Cr > 25% above baselineaBUN/Cr ? 20 CyA serum trough level < 150 ng/mLRapid rise in Cr (> 0.3 mg/dL/day)aBUN/Cr < 20 BiopsyArteriolopathy (medial hypertrophya, hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, progressive scarring)Tubular atrophy, isometric vacuolization, isolated calcificationsMinimal edemaMild focal infiltratescDiffuse interstitial fibrosis, often striped formEndovasculitisc (proliferationa, intimal arteritisb, necrosis, sclerosis)Tubulitis with RBCb and WBCb casts, some irregular vacuolizationInterstital edemac and hemorrhagebDiffuse moderate to severe mononuclear infiltratesdGlomerulitis (mononuclear cells)c 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 HgbIntracapsular pressure > 40 mm Hgb UltrasonographyUnchanged 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(131I-hippuran) > decrease in perfusion (99mTc DTPA)Patchy arterial flowDecrease in perfusion > decrease in tubular functionIncreased uptake of Indium 111 labeled platelets or Tc-99m in colloid TherapyResponds to decreased cyclosporineResponds to increased steroids or antilymphocyte globulin ap< 0.05, bp < 0.01, cp <0.001, dp<0.0001A form of chronic progressive cyclosporine-associated nephrotoxicity is characterized by serial deterioration in renal function and morphologic changes in the kidneys.

From 5% to 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, highdose corticosteriods, 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.Rarely (approximately 1 in 1000), patients receiving cyclosporine injection have experienced anaphylactic reactions.

Although the exact cause of these reactions is unknown, it is believed to be due to the polyoxyethylated castor oil used as the vehicle for the I.V.

formulation.

These reactions can consist of flushing of the face and upper thorax, and non-cardiogenic pulmonary edema, with acute repiratory distress, dyspnea, wheezing, blood pressure changes, and tachycardia.

One patient died after respiratory arrest and aspiration pneumonia.

In some cases, the reaction subsided after the infusion was stopped.Patients receiving cyclosporine injection should be under continuous observation for at leastthe first 30 minutes following the start of the infusion and at frequent intervals thereafter.

If anaphylaxis occurs, the infusion should be stopped.

An aqueous solution of epinephrine 1:1000 should be available at the bedside as well as a source of oxygen.Anaphylactic reactions have not been reported with the soft gelatin capsules or oral solution which lack polyoxyethylated castor oil.

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

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

Conversion from Neoral® to Cyclosporine Injection 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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