INDICATIONS AND USAGE Sandimmune capsules and Sandimmune injection, in combination with adrenal corticosteroids, are indicated for the: Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants.

Treatment of chronic rejection in patients previously treated with other immunosuppressive agents.

Because of the risk of anaphylaxis, Sandimmune injection should be reserved for patients who are unable to take the Sandimmune capsules.

WARNINGS Kidney, Liver, and Heart Transplant Sandimmune, when used in high dosages, can cause hepatotoxicity and nephrotoxicity (see BOXED WARNING) .

Nephrotoxicity It is not unusual for serum creatinine and Blood Urea Nitrogen (BUN) levels to be elevated during Sandimmune 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 Sandimmune 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.

a p < 0.05, b p < 0.01, c p < 0.001, d p < 0.0001.

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 postop b Often < 4 weeks postop b Prolonged initial nonfunction (acute tubular necrosis) 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 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 hypertrophy a , hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, progressive scarring) Endovasculitis c (proliferation a , intimal arteritis b , necrosis, sclerosis) Tubular atrophy, isometric vacuolization, isolated calcifications Tubulitis with RBC b and WBC b casts, some irregular vacuolization Minimal edema Interstitial edema c and hemorrhage b Mild focal infiltrates c Diffuse moderate to severe mononuclear infiltrates d Diffuse interstitial fibrosis, often striped form Glomerulitis (mononuclear cells) c 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 granularization Degenerative tubular cells, plasma cells, and lymphocyturia > 20% of sediment Manometry Intracapsular pressure < 40 mm Hg b Intracapsular pressure > 40 mm Hg b 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 ( 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% 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 are 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 dosage 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 Sandimmune 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 with concomitant administration of Sandimmune 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 Sandimmune 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 dosage of Sandimmune (cyclosporine) were used.

The chemistry elevations usually decreased with a reduction in dosage.

Malignancies As in patients receiving other immunosuppressants, those patients receiving Sandimmune 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, Sandimmune 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 Sandimmune, 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 Sandimmune, 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 Sandimmune.

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-dosage 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-dosage 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 dosage.

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 Rarely (approximately 1 in 1000), patients receiving Sandimmune injection have experienced anaphylactic reactions.

Although the exact cause of these reactions is unknown, it is believed to be due to the Cremophor EL (polyoxyethylated castor oil) used as the vehicle in the Sandimmune injection formulation.

These reactions can consist of flushing of the face and upper thorax, and noncardiogenic pulmonary edema, with acute respiratory 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 Sandimmune injection should be under continuous observation for at least the 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, which lack Cremophor EL (polyoxyethylated castor oil).

In fact, patients experiencing anaphylactic reactions have been treated subsequently with the soft gelatin capsules without incident.

Alcohol (ethanol) The alcohol content (see DESCRIPTION) of Sandimmune should be considered 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 dosage would deliver about 1 gram of alcohol (see DESCRIPTION for alcohol content of each formulation).

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

Risks with Inappropriate Switching Between Neoral Capsules (MODIFIED) and Sandimmune Capsules Do not switch between Sandimmune capsules to Neoral capsules, MODIFIED on a mg-to-mg basis to achieve the same total daily cyclosporine dosage.

Sandimmune (cyclosporine capsules), 25 mg and 100 mg and Neoral (cyclosporine capsules), MODIFIED 25 mg and 100 mg are not mutually substitutable on a mg-to-mg basis due to differences in pharmacokinetic profiles.

Inappropriate switching from Sandimmune capsules to Neoral capsules MODIFIED, increases cyclosporine exposure which may increase the risk of cyclosporine-associated adverse reactions.

Inappropriate switching from Neoral capsules, MODIFIED, to Sandimmune capsules decreases cyclosporine exposure which may decrease the efficacy of cyclosporine for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants or treatment of chronic rejection in patients previously treated with other immunosuppressive agents.

For recommendations on how to switch between Sandimmune capsules and Neoral capsules, including increasing the frequency of blood cyclosporine concentration monitoring, see DOSAGE AND ADMINISTRATION

ADVERSE REACTIONS The principal adverse reactions of Sandimmune 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.

Adverse Reactions in 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 Sandimmune-Treated Patients Sandimmune 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.

Sandimmune was discontinued on a temporary basis and then restarted in 18 additional patients.

Renal Transplant Patients in Whom Therapy Was Discontinued Randomized Patients All Sandimmune-Treated Patients Sandimmune 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 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) .

*Some patients also received ALG.

Infectious Complications in the Randomized Renal Transplant Patients Sandimmune Treatment Standard Treatment* (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 Cremophor ® EL (polyoxyethylated castor oil) is known to cause hyperlipemia and electrophoretic abnormalities of lipoproteins.

These effects are reversible upon discontinuation of treatment but are usually not a reason to stop treatment.

Adverse Reactions During Postmarketing Use 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 health care provider 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.