INDICATIONS AND USAGE 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.

WARNINGS Kidney, Liver, and Heart Transplant Cyclosporine capsules, (NON-MODIFIED), when used in high doses, can cause hepatotoxicity and nephrotoxicity (see Boxed Warning .

) 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 elevations of BUN and creatinine at a range of 35 to 45 mg/dl and 2.0 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 Prolonged anastomosis time Retransplant patient Concomitant nephrotoxic drugs Clinical Often > 6 weeks postop p < 0.05, Often < 4 weeks postop p < 0.01, 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) Rapid rise in Cr (> 0.3 mg/dL/day) Cr plateau < 25% above baseline Cr > 25% above baseline BUN/Cr ≥ 20 BUN/Cr < 20 Biopsy Arteriolopathy (medial hypertrophy , Endovasculitis p < 0.001, (proliferation , hyalinosis, nodular deposits, intimal intimal arteritis , necrosis, sclerosis) thickening, endothelial vacuolization, progressive scarring) Tubular atrophy, isometric vacuolization, Tubulitis with RBC and WBC casts, isolated calcifications some irregular vacuolization Minimal edema Interstitial edema and hemorrhage Mild focal infiltrates Diffuse moderate to severe mononuclear infiltrates p < 0.0001 Diffuse interstitial fibrosis, often striped form Glomerulitis (mononuclear cells) Aspiration Cytology CyA deposits in tubular and endothelial cells Inflammatory infiltrate with mononuclear phagocytes, 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 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 Patchy arterial flow Decrease in tubular function Decrease in perfusion > decrease in tubular function ( 131 I-hippuran) > decrease in perfusion Increased uptake of Indium 111 labeled platelets or Tc-99m in colloid ( 99m Tc DTPA) Therapy Responds to decreased cyclosporine capsules 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% 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 (see PRECAUTIONS, Drug Interactions ).

Thrombotic Microangiopathy 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 (see ADVERSE REACTIONS ).

Hyperkalemia Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.

Hepatotoxicity 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 (see ADVERSE REACTIONS, Postmarketing Experience ).

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.

Malignancies 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.

Serious Infections 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 (see BOXED WARNING , and ADVERSE REACTIONS ).

Polyoma Virus Infections 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, (see ADVERSE REACTIONS, Postmarketing Experience ).

Patient monitoring may help detect patients at risk for PVAN.

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.

Neurotoxicity 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.

Specific Excipients Alcohol (methanol) The alcohol content (see DESCRIPTION ) of cyclosporine capsules should be taken into account when given to patients in whom alcohol intake should be avoided or minimized, e.g.

pregnant or breastfeeding women, in patients presenting with liver disease or epilepsy, in alcoholic patients, or pediatric patients.

For an adult weighing 70 kg, the maximum daily oral dose would deliver about 1 gram of alcohol.

(See DESCRIPTION for alcohol content of each formulation).

Care should be taken in using cyclosporine capsules with nephrotoxic drugs (see PRECAUTIONS ).

Conversion from Neoral to Cyclosporine capsules 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.

ADVERSE REACTIONS 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.

Clinical Studies 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 (see WARNINGS ).

Infectious Complications in the Randomized Renal Transplant Patients Cyclosporine capsules Treatment Standard Treatment Some 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 Postmarketing Experience Hepatotoxicity Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported (see WARNINGS, Hepatotoxicity ).

Increased Risk of Infections Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported (see WARNINGS, Polyoma Virus Infection ).

Headache, Including Migraine Cases of migraine have been reported.

In some cases, patients have been unable to continue cyclosporine, however, the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks.

Pain of Lower Extremities Isolated cases of pain of lower extremities have been reported in association with cyclosporine.

Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature.