Cyclosporine Solution

Cyclosporine Solution

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Questions & Answers

Side Effects & Adverse Reactions

(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
Parameter Nephrotoxicity Rejection
*
p < 0.01
p < 0.05
p < 0.001
§
p < 0.0001
History Donor > 50 years old or hypotensive
Prolonged kidney preservation
Prolonged anastomosis time
Concomitant nephrotoxic drugs
Antidonor immune response
Retransplant patient
Clinical Often > 6 weeks postop*
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)†
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, progressive scarring) Endovasculitis‡ (proliferation† , intimal arteritis*, necrosis, sclerosis)
Tubular atrophy, isometric vacuolization, isolated calcifications Tubulitis with RBC* and WBC* casts, some irregular vacuolization
Minimal edema Interstitial edema‡ and hemorrhage*
Mild focal infiltrates‡ Diffuse moderate to severe mononuclear infiltrates§
Diffuse interstitial fibrosis, often striped form Glomerulitis (mononuclear cells)‡
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*
Ultra-sonography 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
(131 I-hippuran) > decrease in perfusion
Patchy arterial flow
Decrease in perfusion > decrease in tubular function
(99m Tc DTPA) 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 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. 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. 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 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®1(cyclosporine [MODIFIED]), conversion from Neoral®1 (cyclosporine [MODIFIED]) to cyclosporine using a 1:1 ratio (mg/kg/day) may result in a lower cyclosporine blood concentration. Conversion from Neoral®1 (cyclosporine [MODIFIED]) to cyclosporine should be made with increased blood concentration monitoring to avoid the potential of underdosing.

Legal Issues

There is currently no legal information available for this drug.

FDA Safety Alerts

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Manufacturer Warnings

There is currently no manufacturer warning information available for this drug.

FDA Labeling Changes

There are currently no FDA labeling changes available for this drug.

Uses

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.

History

There is currently no drug history available for this drug.

Other Information

Cyclosporine, the active principle in Cyclosporine Oral Solution, USP is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.

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-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).

Cyclosporine Oral Solution, USP is available in 50 mL bottles.

Each mL contains:
Cyclosporine, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 mg
Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.5% by volume
Dissolved in an olive oil, NF/Labrafil M 1944 CS (polyoxyethylated oleic glycerides) vehicle which must be further diluted with milk, chocolate milk, or orange juice before oral administration.

The chemical structure of cyclosporine (also known as cyclosporine A) is:

Chemical Structure

Cyclosporine Solution Manufacturers


  • Morton Grove Pharmaceuticals, Inc.
    Cyclosporine Solution [Morton Grove Pharmaceuticals, Inc.]
  • Ivax Pharmaceuticals, Inc.
    Cyclosporine Solution [Ivax Pharmaceuticals, Inc.]

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