Cyclosporine Prescribing Information
Cyclosporine capsules, (NON-MODIFIED) have decreased bioavailability in comparison to Neoral®* (cyclosporine capsules, USP) MODIFIED. Cyclosporine capsules, (NON-MODIFIED) and Neoral®* (cyclosporine capsules, USP) MODIFIED are not bioequivalent and cannot be used interchangeably without physician supervision.
The initial oral dose of cyclosporine capsules, (NON-MODIFIED) should be given 4 to 12 hours prior to transplantation as a single dose of 15 mg/kg. Although a daily single dose of 14 to 18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale. There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day. The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day. Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate.
See Blood Concentration Monitoring, below.
Renal Impairment
Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatmentsHepatic Impairment
The clearance of cyclosporine may be significantly reduced in severe liver disease patients
In pediatric usage, the same dose and dosing regimen may be used as in adults although in several studies, children have required and tolerated higher doses than those used in adults.
Adjunct therapy with adrenal corticosteroids is recommended. Different tapering dosage schedules of prednisone appear to achieve similar results. A dosage schedule based on the patient’s weight started with 2 mg/kg/day for the first 4 days tapered to 1 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Another center started with an initial dose of 200 mg tapered by 40 mg/day until reaching 20 mg/day. After 2 months at this dose, a further reduction to 10 mg/day was made. Adjustments in dosage of prednisone must be made according to the clinical situation.
Several study centers have found blood concentration 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 concentrations of 100 to 200 ng/mL as determined by high-pressure liquid chromatography (HPLC).
Of major importance to blood concentration analysis is the type of assay used. The above concentrations 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 concentrations 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, concentrations will vary with the temperature at the time of separation from whole blood. Plasma concentrations may range from 1/2 to 1/5 of whole blood concentrations. Refer to individual assay labeling for complete instructions. In addition,
Several study centers have found blood concentration 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 concentrations of 100 to 200 ng/mL as determined by high-pressure liquid chromatography (HPLC).
Of major importance to blood concentration analysis is the type of assay used. The above concentrations 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 concentrations 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, concentrations will vary with the temperature at the time of separation from whole blood. Plasma concentrations may range from 1/2 to 1/5 of whole blood concentrations. Refer to individual assay labeling for complete instructions. In addition,
Cyclosporine capsules, (NON-MODIFIED) are 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.
Cyclosporine capsules are contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.
The principal adverse reactions of cyclosporine capsules therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.
Hypertension
Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients.
Glomerular Capillary Thrombosis
Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to graft failure. The pathologic changes resemble those seen in the hemolytic-uremic syndrome and include thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function. Similar findings have been observed when other immunosuppressives have been employed post transplantation.
Hypomagnesemia
Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on cyclosporine therapy. Although magnesium-depletion studies in normal subjects suggest that hypomagnesemia is associated with neurologic disorders, multiple factors, including hypertension, high-dose methylprednisolone, hypocholesterolemia, and nephrotoxicity associated with high plasma concentrations of cyclosporine appear to be related to the neurological manifestations of cyclosporine toxicity.
The following reactions occurred in 3% or greater of 892 patients involved in clinical trials of
kidney, heart, and liver transplants:Randomized Kidney Patients | All Cyclosporine capsules Patients | ||||
Cyclosporine capsules | Azathioprine | Kidney | Heart | Liver | |
Body System/ | (N=227) | (N=228) | (N=705) | (N=112) | (N=75) |
Adverse Reactions | % | % | % | % | % |
| Genitourinary | |||||
| Renal Dysfunction | 32 | 6 | 25 | 38 | 37 |
| Cardiovascular | |||||
| Hypertension | 26 | 18 | 13 | 53 | 27 |
| Cramps | 4 | < 1 | 2 | < 1 | 0 |
| Skin | |||||
| Hirsutism | 21 | < 1 | 21 | 28 | 45 |
| Acne | 6 | 8 | 2 | 2 | 1 |
| Central Nervous System | |||||
| Tremor | 12 | 0 | 21 | 31 | 55 |
| Convulsions | 3 | 1 | 1 | 4 | 5 |
| Headache | 2 | < 1 | 2 | 15 | 4 |
| Gastrointestinal | |||||
| Gum Hyperplasia | 4 | 0 | 9 | 5 | 16 |
| Diarrhea | 3 | < 1 | 3 | 4 | 8 |
| Nausea/Vomiting | 2 | < 1 | 4 | 10 | 4 |
| Hepatotoxicity | < 1 | < 1 | 4 | 7 | 4 |
| Abdominal Discomfort | < 1 | 0 | < 1 | 7 | 0 |
| Autonomic Nervous System | |||||
| Paresthesia | 3 | 0 | 1 | 2 | 1 |
| Flushing | < 1 | 0 | 4 | 0 | 4 |
| Hematopoietic | |||||
| Leukopenia | 2 | 19 | < 1 | 6 | 0 |
| Lymphoma | < 1 | 0 | 1 | 6 | 1 |
| Respiratory | |||||
| Sinusitis | < 1 | 0 | 4 | 3 | 7 |
| Miscellaneous | |||||
| Gynecomastia | < 1 | 0 | < 1 | 4 | 3 |
The following reactions occurred in 2% or less of patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia, tinnitus.
The following reactions occurred rarely: anxiety, chest pain, constipation, depression, hair breaking, hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness, weight loss.
Renal Transplant Patients in Whom Therapy Was Discontinued | |||
Randomized Patients | All Cyclosporine capsules Patients | ||
Cyclosporine capsules | Azathioprine | ||
(N=227) | (N=228) | (N=705) | |
Reason for Discontinuation | % | % | % |
| Renal Toxicity | 5.7 | 0 | 5.4 |
| Infection | 0 | 0.4 | 0.9 |
| Lack of Efficacy | 2.6 | 0.9 | 1.4 |
| Acute Tubular Necrosis | 2.6 | 0 | 1.0 |
| Lymphoma/Lymphoproliferative Disease | 0.4 | 0 | 0.3 |
| Hypertension | 0 | 0 | 0.3 |
| Hematological Abnormalities | 0 | 0.4 | 0 |
| Other | 0 | 0 | 0.7 |
| Cyclosporine capsules was discontinued on a temporary basis and then restarted in 18 additional patients. | |||
Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine-containing regimens, are at increased risk of infections (viral, bacterial, fungal, and parasitic). Both generalized and localized infections can occur. Preexisting infections may also be aggravated. Fatal outcomes have been reported
Cyclosporine capsules, (NON-MODIFIED), when used in high doses, can cause hepatotoxicity and nephrotoxicity
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 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 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 capsules 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 |
| History | Donor > 50 years old or hypotensive | Antidonor immune response |
| Prolonged kidney preservation | Retransplant patient | |
| Prolonged anastomosis time | ||
| Concomitant nephrotoxic drugs | ||
| Clinical | Often > 6 weeks postopb | Often < 4 weeks postopb |
| Prolonged initial nonfunction | Fever > 37.5°C | |
| (acute tubular necrosis) | 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 | CyA serum trough level < 150 ng/mL |
| Gradual rise in Cr (< 0.15 mg/dL/day)a | Rapid rise in Cr (> 0.3 mg/dL/day)a | |
| Cr plateau < 25% above baseline | Cr > 25% above baseline | |
| BUN/Cr ≥ 20 | BUN/Cr < 20 | |
| Biopsy | Arteriolopathy (medial hypertrophya, | Endovasculitisc(proliferationa, |
| hyalinosis, nodular deposits, intimal | intimal arteritisb, necrosis, sclerosis) | |
| thickening, endothelial vacuolization, | ||
| progressive scarring) | ||
| Tubular atrophy, isometric vacuolization, | Tubulitis with RBCband WBCbcasts, | |
| isolated calcifications | some irregular vacuolization | |
| Minimal edema | Interstitial edemacand hemorrhageb | |
| Mild focal infiltratesc | Diffuse moderate to severe mononuclear | |
| infiltratesd | ||
| Diffuse interstitial fibrosis, | Glomerulitis (mononuclear cells)c | |
| often striped form | ||
| Aspiration Cytology | CyA deposits in tubular and | Inflammatory infiltrate with mononuclear phagocytes, |
| endothelial cells | macrophages, lymphoblastoid cells, and | |
| activated T-cells | ||
| Fine isometric vacuolization of | ||
| tubular cells | ||
| These strongly express HLA-DR antigens | ||
| Urine Cytology | Tubular cells with vacuolization and | Degenerative tubular cells, plasma cells, and |
| granularization | lymphocyturia > 20% of sediment | |
| Manometry | Intracapsular pressure < 40 mm Hgb | Intracapsular pressure > 40 mm Hgb |
| Ultrasonography | Unchanged graft cross-sectional area | Increase in graft cross-sectional area |
| AP diameter ≥ Transverse diameter | ||
| Magnetic Resonance | Normal appearance | Loss of distinct corticomedullary junction, swelling, |
| Imagery | image intensity of parachyma approaching that | |
| of psoas, loss of hilar fat | ||
| Radionuclide Scan | Normal or generally decreased perfusion | Patchy arterial flow |
| Decrease in tubular function | Decrease in perfusion > decrease in tubular function | |
| (131I-hippuran) > decrease in perfusion | Increased uptake of Indium 111 labeled platelets or | |
| (99mTc DTPA) | Tc-99m in colloid | |
| Therapy | Responds to decreased | Responds to increased steroids or |
| cyclosporine capsules | antilymphocyte globulin | |
ap < 0.05,bp < 0.01,cp < 0.001,dp < 0.0001
A 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 concentrations 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 capsules dosage to a very high level in an attempt to reverse the rejection.
Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering cyclosporine capsules with other drugs that may impair renal function
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 capsules and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans
Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.
Cases of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, and liver failure have been reported in patients treated with cyclosporine. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors, including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported
Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, was reported in patients treated with cyclosporine in clinical trials: 4% in renal transplantation, 7% in cardiac transplantation, and 4% in liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine capsules were used. The chemistry elevations usually decreased with a reduction in dosage.
As in patients receiving other immunosuppressants, those patients receiving cyclosporine capsules 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 capsules 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.
Patients receiving immunosuppressants, including cyclosporine capsules, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes
Patients receiving immunosuppressants, including cyclosporine capsules, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes, fatal outcomes. These include cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), and polyoma virus-associated nephropathy (PVAN), especially due to BK virus infection, which have been observed in patients receiving cyclosporine.
PVAN is associated with serious outcomes, including deteriorating renal function and renal graft loss,
Cases of PML have been reported in patients treated with cyclosporine capsules. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.
Consideration should be given to reducing the total immunosuppression in transplant patients who develop PML or PVAN. However, reduced immunosuppression may place the graft at risk.
There have been reports of convulsions in adult and pediatric patients receiving cyclosporine, particularly in combination with high-dose methylprednisolone.
Encephalopathy, including Posterior Reversible Encephalopathy Syndrome (PRES), 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.
Care should be taken in using cyclosporine capsules with nephrotoxic drugs
Because cyclosporine capsules (NON-MODIFIED), is not bioequivalent to Neoral®*, conversion from Neoral®* to cyclosporine capsules, (NON-MODIFIED) using a 1:1 ratio (mg/kg/day) may result in a lower cyclosporine blood concentration. Conversion from Neoral®* to cyclosporine capsules, (NON-MODIFIED) should be made with increased blood concentration monitoring to avoid the potential of underdosing.
Infectious Complications in the Randomized Renal Transplant Patients | ||
| Cyclosporine capsules Treatment | Standard TreatmentSome patients also received ALG. | |
(N=227) | (N=228) | |
Complication | % of Complications | % of Complications |
| Septicemia | 5.3 | 4.8 |
| Abscesses | 4.4 | 5.3 |
| Systemic Fungal Infection | 2.2 | 3.9 |
| Local Fungal Infection | 7.5 | 9.6 |
| Cytomegalovirus | 4.8 | 12.3 |
| Other Viral Infections | 15.9 | 18.4 |
| Urinary Tract Infections | 21.1 | 20.2 |
| Wound and Skin Infections | 7.0 | 10.1 |
| Pneumonia | 6.2 | 9.2 |
All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) 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 capsules, (NON-MODIFIED), when used in high doses, can cause hepatotoxicity and nephrotoxicity
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 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 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 capsules 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 |
| History | Donor > 50 years old or hypotensive | Antidonor immune response |
| Prolonged kidney preservation | Retransplant patient | |
| Prolonged anastomosis time | ||
| Concomitant nephrotoxic drugs | ||
| Clinical | Often > 6 weeks postopb | Often < 4 weeks postopb |
| Prolonged initial nonfunction | Fever > 37.5°C | |
| (acute tubular necrosis) | 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 | CyA serum trough level < 150 ng/mL |
| Gradual rise in Cr (< 0.15 mg/dL/day)a | Rapid rise in Cr (> 0.3 mg/dL/day)a | |
| Cr plateau < 25% above baseline | Cr > 25% above baseline | |
| BUN/Cr ≥ 20 | BUN/Cr < 20 | |
| Biopsy | Arteriolopathy (medial hypertrophya, | Endovasculitisc(proliferationa, |
| hyalinosis, nodular deposits, intimal | intimal arteritisb, necrosis, sclerosis) | |
| thickening, endothelial vacuolization, | ||
| progressive scarring) | ||
| Tubular atrophy, isometric vacuolization, | Tubulitis with RBCband WBCbcasts, | |
| isolated calcifications | some irregular vacuolization | |
| Minimal edema | Interstitial edemacand hemorrhageb | |
| Mild focal infiltratesc | Diffuse moderate to severe mononuclear | |
| infiltratesd | ||
| Diffuse interstitial fibrosis, | Glomerulitis (mononuclear cells)c | |
| often striped form | ||
| Aspiration Cytology | CyA deposits in tubular and | Inflammatory infiltrate with mononuclear phagocytes, |
| endothelial cells | macrophages, lymphoblastoid cells, and | |
| activated T-cells | ||
| Fine isometric vacuolization of | ||
| tubular cells | ||
| These strongly express HLA-DR antigens | ||
| Urine Cytology | Tubular cells with vacuolization and | Degenerative tubular cells, plasma cells, and |
| granularization | lymphocyturia > 20% of sediment | |
| Manometry | Intracapsular pressure < 40 mm Hgb | Intracapsular pressure > 40 mm Hgb |
| Ultrasonography | Unchanged graft cross-sectional area | Increase in graft cross-sectional area |
| AP diameter ≥ Transverse diameter | ||
| Magnetic Resonance | Normal appearance | Loss of distinct corticomedullary junction, swelling, |
| Imagery | image intensity of parachyma approaching that | |
| of psoas, loss of hilar fat | ||
| Radionuclide Scan | Normal or generally decreased perfusion | Patchy arterial flow |
| Decrease in tubular function | Decrease in perfusion > decrease in tubular function | |
| (131I-hippuran) > decrease in perfusion | Increased uptake of Indium 111 labeled platelets or | |
| (99mTc DTPA) | Tc-99m in colloid | |
| Therapy | Responds to decreased | Responds to increased steroids or |
| cyclosporine capsules | antilymphocyte globulin | |
ap < 0.05,bp < 0.01,cp < 0.001,dp < 0.0001
A 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 concentrations 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 capsules dosage to a very high level in an attempt to reverse the rejection.
Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering cyclosporine capsules with other drugs that may impair renal function
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 capsules and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans
Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.
Cases of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, and liver failure have been reported in patients treated with cyclosporine. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors, including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported
Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, was reported in patients treated with cyclosporine in clinical trials: 4% in renal transplantation, 7% in cardiac transplantation, and 4% in liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine capsules were used. The chemistry elevations usually decreased with a reduction in dosage.
As in patients receiving other immunosuppressants, those patients receiving cyclosporine capsules 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 capsules 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.
Patients receiving immunosuppressants, including cyclosporine capsules, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes
Patients receiving immunosuppressants, including cyclosporine capsules, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes, fatal outcomes. These include cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), and polyoma virus-associated nephropathy (PVAN), especially due to BK virus infection, which have been observed in patients receiving cyclosporine.
PVAN is associated with serious outcomes, including deteriorating renal function and renal graft loss,
Cases of PML have been reported in patients treated with cyclosporine capsules. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.
Consideration should be given to reducing the total immunosuppression in transplant patients who develop PML or PVAN. However, reduced immunosuppression may place the graft at risk.
There have been reports of convulsions in adult and pediatric patients receiving cyclosporine, particularly in combination with high-dose methylprednisolone.
Encephalopathy, including Posterior Reversible Encephalopathy Syndrome (PRES), 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.
Care should be taken in using cyclosporine capsules with nephrotoxic drugs
Because cyclosporine capsules (NON-MODIFIED), is not bioequivalent to Neoral®*, conversion from Neoral®* to cyclosporine capsules, (NON-MODIFIED) using a 1:1 ratio (mg/kg/day) may result in a lower cyclosporine blood concentration. Conversion from Neoral®* to cyclosporine capsules, (NON-MODIFIED) should be made with increased blood concentration monitoring to avoid the potential of underdosing.
Cyclosporine, USP, the active principle in cyclosporine capsules, USP (NON-MODIFIED) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species
Chemically, cyclosporine is designated as [
Cyclosporine capsules, USP (NON-MODIFIED) are available in 25 mg and 100 mg strengths.
Each 25 mg capsule contains:
Cyclosporine, USP……………………………………………………………………...25 mg
Each 100 mg capsule contains:
Cyclosporine, USP……………………………………………………..……………...100 mg
Each capsule contains the following inactive ingredients: methanol, sodium lauryl sulfate and talc. The 25 mg and the 100 mg capsule shell contains gelatin, red iron oxide and titanium dioxide.
The 25 mg and 100 mg capsule black imprinting ink contains the following inactive ingredients: n-butyl alcohol, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #40 aluminum lake, pharmaceutical glaze, propylene glycol, SDA-3A alcohol and synthetic black iron oxide.
The chemical structure of cyclosporine (also known as cyclosporin A) is:
