FDA label 219a91ef-5834-29ad-e054-00144ff88e88

WARNING Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Cyclosporine Capsules USP NON-MODIFIED. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Cyclosporine Capsules USP NON-MODIFIED should be administered with adrenal corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

Cyclosporine Soft Gelatin Capsules USP (NON-MODIFIED) have decreased bioavailability in comparison to Neoral®* (cyclosporine capsules, USP) MODIFIED. Cyclosporine Capsules USP (NON-MODIFIED) and Neoral® (cyclosporine capsules, USP) MODIFIED are not bioequivalent and cannot be used interchangeably without physician supervision. The absorption of cyclosporine during chronic administration Cyclosporine Capsules USP NON-MODIFIED was found to be erratic. It is recommended that patients taking Cyclosporine Capsules USP NON-MODIFIED over a period of time be monitored at repeated intervals for cyclosporine blood levels and subsequent dose adjustments be made in order to avoid toxity due to high levels and possible organ rejection due to low absorption of cyclosporine. This is of special importance in liver transplants. Numerous assays are being developed to measure blood levels of cyclosporine. Comparison of levels in published literature to patient levels using current assays must be done with detailed knowledge of the assay methods employed. (See Blood Level Monitoring under DOSAGE AND ADMINISTRATION )

Antibiotics: ciprofoxacin, gentamicin, tobramycin, vancomycin, tremethoprim with sulfamethoxazole Antineoplastic: melphalan Antifungals:amphotericin B, ketoconazole Anti-Inflammatory Drugs: azapropazon, colchicine, diclofenac, naproxen, sulindac Gastrointestinal Agents: cimetidine, ranitidine Immunosuppressives: tacrolimus Other Drugs: fibric acid derivatives (e.g., bezafibrate, fenofibrate)

Calcium Channel Blockers: diltiazem, nicardipine,verapamil Antifungals: fluconazole, intraconazole, ketoconazole Antibiotics: azithromycin, clarithromycin, erythromycin, quinupristin/dalfopristin Glucocorticoids: methylprednisolone

WARNINGS (See boxed WARNINGS ): Cyclosporine Capsules USP NON-MODIFIED, 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 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 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 RBCb and WBCb casts, isolated calcifications some irregular vacuolization Minimal edema Interstitial edemac and 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 (131 I-hippuran) > decrease in perfusion Increased uptake of Indium 111 labeled platelets or (99m Tc DTPA) Tc-99m in colloid Therapy Responds to decreased Sandimmune® Responds to increased steroids or (cyclosporine) antilymphocyte globulin a p < 0.05, b p < 0.01, c p < 0.001, d p < 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 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 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 with nephrotoxic drugs. (See PRECAUTIONS .) Because Cyclosporine Capsules USP NON-MODIFIED is not bioequivalent to Neoral®*, conversion from Neoral®* to Cyclosporine Capsules USP NON-MODIFIED using a 1:1 ratio (mg/kg/day) may result in a lower cyclosporine blood concentration. Conversion from Neoral®* to Cyclosporine Capsules USP NON-MODIFIED should be made with increased blood concentration monitoring to avoid the potential of underdosing.

<table border="none" width="434" ID="id_b169941c-cb5b-465f-b0f4-089e0082a303"> <col width="22.4%"/> <col width="37.1%"/> <col width="40.6%"/> <tbody> <tr ID="id_95f8ea97-fce4-4a30-ac01-1f98404d4755"> <td align="left" styleCode="Toprule" valign="bottom"/> <td align="center" colspan="2" valign="bottom"> <content styleCode="bold">Nephrotoxicity vs. Rejection</content> </td> </tr> <tr ID="id_824e1a23-19c6-4d61-864d-d4a591d36e81"> <td align="left" valign="bottom"> <content styleCode="bold">Parameter</content> </td> <td align="left" valign="bottom"> <content styleCode="bold">Nephrotoxicity</content> </td> <td align="left" valign="bottom"> <content styleCode="bold">Rejection</content> </td> </tr> <tr ID="id_fbcd4c9e-c638-4211-be85-0239d7d36ae4"> <td align="left" valign="bottom">History</td> <td align="left" valign="bottom">Donor &gt; 50 years old or hypotensive</td> <td align="left" valign="bottom">Antidonor immune response</td> </tr> <tr ID="id_875b3ab7-1f9b-4853-8d76-122a62435c59"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Prolonged kidney preservation</td> <td align="left" valign="bottom">Retransplant patient</td> </tr> <tr ID="id_eb6daf00-33ae-4061-9577-ce1ddc03e602"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Prolonged anastomosis time</td> <td align="left" valign="bottom"/> </tr> <tr ID="id_a005d0d0-b672-4909-80b7-f405ebcfedd2"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Concomitant nephrotoxic drugs</td> <td align="left" valign="bottom"/> </tr> <tr ID="id_d24cb20d-e76d-48e8-ab1b-3a1732c968f9"> <td align="left" valign="bottom">Clinical</td> <td align="left" valign="bottom">Often &gt; 6 weeks postopb</td> <td align="left" valign="bottom">Often &lt; 4 weeks postopb</td> </tr> <tr ID="id_a9e64683-ea7f-4602-a8d5-981d7bdb5d3c"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Prolonged initial nonfunction </td> <td align="left" valign="bottom">Fever &gt; 37.5&#xB0;C</td> </tr> <tr ID="id_dba426ca-817a-4e7a-b0fe-4ecd1af06e28"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">(acute tubular necrosis) </td> <td align="left" valign="bottom">Weight gain &gt; 0.5 kg</td> </tr> <tr ID="id_c2d55bf8-cdcf-4bd8-8f1a-03941f8dac08"> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Graft swelling and tenderness</td> </tr> <tr ID="id_02c8e9b0-3b4e-4e1a-9a72-27f867c5e0bd"> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Decrease in daily urine volume &gt; 500 mL </td> </tr> <tr ID="id_94c1e036-70a9-46a1-b25d-30ff8f4dbd7d"> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom">(or 50%)</td> </tr> <tr ID="id_6a703dd6-1451-4110-a4a5-00cc3122a3dd"> <td align="left" valign="bottom">Laboratory</td> <td align="left" valign="bottom"> <paragraph>CyA serum trough level &gt; </paragraph> <paragraph>200 ng/mL</paragraph> </td> <td align="left" valign="bottom">CyA serum trough level &lt; 150 ng/mL</td> </tr> <tr ID="id_a6e5bb84-8a62-41a8-8b33-31568047f927"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Gradual rise in Cr (&lt; 0.15 mg/dl/day)a</td> <td align="left" valign="bottom">Rapid rise in Cr (&gt; 0.3 mg/dl/day)a</td> </tr> <tr ID="id_4987cfa4-8d5f-4344-8fe3-507b12a82f95"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Cr plateau &lt; 25% above baseline</td> <td align="left" valign="bottom">Cr &gt; 25% above baseline</td> </tr> <tr ID="id_a4d74a9e-1afc-4f60-8ab1-1ff4ed234a86"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">BUN/Cr &#x2265; 20</td> <td align="left" valign="bottom">BUN/Cr &lt; 20</td> </tr> <tr ID="id_df78873e-d177-4c31-831f-b4c724fd818c"> <td align="left" valign="bottom">Biopsy</td> <td align="left" valign="bottom">Arteriolopathy (medial hypertrophya, </td> <td align="left" valign="bottom">Endovasculitisc (proliferationa, </td> </tr> <tr ID="id_340a5813-f990-43e9-8317-628c3238d992"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">hyalinosis, nodular deposits, intimal </td> <td align="left" valign="bottom">intimal arteritisb, necrosis, sclerosis)</td> </tr> <tr ID="id_2f9b8042-c165-433a-927d-5671e61ad6d3"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">thickening, endothelial vacuolization,</td> <td align="left" valign="bottom"/> </tr> <tr ID="id_194788ee-8e15-4712-a093-4327647f724e"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">progressive scarring)</td> <td align="left" valign="bottom"/> </tr> <tr ID="id_84f41456-1e0e-45ef-aa7c-b4b313afb4da"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Tubular atrophy, isometric vacuolization, </td> <td align="left" valign="bottom">Tubulitis with RBCb and WBCb casts, </td> </tr> <tr ID="id_be3322e5-e809-4fff-8025-3c416eeb4b23"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">isolated calcifications</td> <td align="left" valign="bottom">some irregular vacuolization</td> </tr> <tr ID="id_6fbb08ae-d940-4337-89ec-0b0d44f74828"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Minimal edema</td> <td align="left" valign="bottom">Interstitial edemac and hemorrhageb</td> </tr> <tr ID="id_8b6e3662-c1d7-4c03-b829-77d365330fb6"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Mild focal infiltratesc</td> <td align="left" valign="bottom">Diffuse moderate to severe mononuclear </td> </tr> <tr ID="id_a70fa626-ce34-4562-a4ea-d97349a9dcf1"> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom">infiltratesd</td> </tr> <tr ID="id_628d21a7-dc57-432d-99ed-74919fef6cde"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Diffuse interstitial fibrosis,</td> <td align="left" valign="bottom">Glomerulitis (mononuclear cells)c</td> </tr> <tr ID="id_99e38083-76d8-40f8-9b6c-e4ed0c0d8637"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">often striped form</td> <td align="left" valign="bottom"/> </tr> <tr ID="id_e72a3727-a460-402f-a390-ec1b59c255ec"> <td align="left" valign="bottom">Aspiration Cytology</td> <td align="left" valign="bottom">CyA deposits in tubular and </td> <td align="left" valign="bottom">Inflammatory infiltrate with mononuclear phagocytes,</td> </tr> <tr ID="id_e1db873f-a140-4cd6-ba74-d314388c856e"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">endothelial cells</td> <td align="left" valign="bottom">macrophages, lymphoblastoid cells, and</td> </tr> <tr ID="id_35a6ea80-bd48-4d36-8bb0-b83960f18584"> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom">activated T-cells</td> </tr> <tr ID="id_434210a9-bf11-414e-b60a-4a38056e5657"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Fine isometric vacuolization of </td> <td align="left" valign="bottom"/> </tr> <tr ID="id_c3dfe5e5-ec46-4039-9da7-e6da6d30e748"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">tubular cells </td> <td align="left" valign="bottom"/> </tr> <tr ID="id_2f15b6a9-4a21-4895-b3c4-e8b5bdfd76b5"> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom">These strongly express HLA-DR antigens</td> </tr> <tr ID="id_f9228a5a-884f-4fc6-bc00-95347df0a4c1"> <td align="left" valign="bottom">Urine Cytology</td> <td align="left" valign="bottom">Tubular cells with vacuolization and </td> <td align="left" valign="bottom">Degenerative tubular cells, plasma cells, and </td> </tr> <tr ID="id_1d6a5aa0-c708-48c8-9dae-81af209272a0"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">granularization</td> <td align="left" valign="bottom">lymphocyturia &gt; 20% of sediment</td> </tr> <tr ID="id_3529f6d5-18bd-4d78-b2ba-6a254477aea8"> <td align="left" valign="bottom">Manometry</td> <td align="left" valign="bottom">Intracapsular pressure &lt; 40 mm Hgb</td> <td align="left" valign="bottom">Intracapsular pressure &gt; 40 mm Hgb</td> </tr> <tr ID="id_d0ede6ce-ef61-4230-b065-fffb9b2fdb95"> <td align="left" valign="bottom">Ultrasonography</td> <td align="left" valign="bottom">Unchanged graft cross-sectional area</td> <td align="left" valign="bottom">Increase in graft cross-sectional area</td> </tr> <tr ID="id_17100907-0368-437d-87a6-92fef6f724d4"> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom">AP diameter &#x2265; Transverse diameter</td> </tr> <tr ID="id_8d932a97-b2db-4624-93e2-de35f48bcf8e"> <td align="left" valign="bottom">Magnetic Resonance </td> <td align="left" valign="bottom">Normal appearance</td> <td align="left" valign="bottom">Loss of distinct corticomedullary junction, swelling, </td> </tr> <tr ID="id_f9344e3d-7419-454d-9a32-2619710372bf"> <td align="left" valign="bottom">Imagery</td> <td align="left" valign="bottom"/> <td align="left" valign="bottom">image intensity of parachyma approaching that </td> </tr> <tr ID="id_9a090942-dd2e-48b7-b49a-1a439089cd35"> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom">of psoas, loss of hilar fat</td> </tr> <tr ID="id_4195ed6c-ad89-4658-87c7-bc46197fd297"> <td align="left" valign="bottom">Radionuclide Scan</td> <td align="left" valign="bottom">Normal or generally decreased perfusion</td> <td align="left" valign="bottom">Patchy arterial flow</td> </tr> <tr ID="id_ad0a1d72-a296-468c-b8d8-00b49a9d98ec"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">Decrease in tubular function </td> <td align="left" valign="bottom">Decrease in perfusion &gt; decrease in tubular function</td> </tr> <tr ID="id_fcf81f3d-135e-4c32-aebb-e011eb844c38"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">(131 I-hippuran) &gt; decrease in perfusion </td> <td align="left" valign="bottom">Increased uptake of Indium 111 labeled platelets or </td> </tr> <tr ID="id_236026de-3e84-4726-95b9-f7ccb08718f3"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">(99m Tc DTPA)</td> <td align="left" valign="bottom">Tc-99m in colloid</td> </tr> <tr ID="id_620f31d2-b133-4566-9fc6-a918cffd452c"> <td align="left" valign="bottom">Therapy</td> <td align="left" valign="bottom">Responds to decreased Sandimmune&#xAE; </td> <td align="left" valign="bottom">Responds to increased steroids or</td> </tr> <tr ID="id_5fb861b2-0439-4983-8dd1-29914741aeaa"> <td align="left" valign="bottom"/> <td align="left" valign="bottom">(cyclosporine)</td> <td align="left" valign="bottom">antilymphocyte globulin</td> </tr> </tbody> </table>

ADVERSE REACTIONS The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia. 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 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 posttransplantation. 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 Patients Cyclosporine 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 Patients Cyclosporine 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 was discontinued on a temporary basis and then restarted in 18 additional patients. Infectious Complications in the Randomized Renal Transplant Patients Cyclosporine 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 *Some patients also received ALG.

<table border="none" width="438" ID="id_c62c0c60-0475-41a1-9f1c-d89238d0222e"> <col width="28.8%"/> <col width="16.2%"/> <col width="16.2%"/> <col width="12.6%"/> <col width="13.7%"/> <col width="12.6%"/> <tbody> <tr ID="id_44df8b7b-6413-49cb-be7a-0c74cd34126e"> <td align="left" styleCode="Toprule" valign="bottom"/> <td align="center" colspan="2" styleCode="Toprule" valign="bottom">Randomized Kidney Patients </td> <td align="center" colspan="3" valign="bottom">All Cyclosporine Patients </td> </tr> <tr ID="id_6ce07791-8631-4e51-8723-9371d06edd13"> <td align="left" valign="bottom"/> <td align="center" valign="bottom">Cyclosporine</td> <td align="center" valign="bottom">Azathioprine</td> <td align="center" valign="bottom">Kidney</td> <td align="center" valign="bottom">Heart</td> <td align="center" valign="bottom">Liver</td> </tr> <tr ID="id_84f22663-8880-4c30-b298-77246c76800a"> <td align="left" valign="bottom">Body System/</td> <td align="center" valign="bottom">(N=227)</td> <td align="center" valign="bottom">(N=228)</td> <td align="center" valign="bottom">(N=705)</td> <td align="center" valign="bottom">(N=112)</td> <td align="center" valign="bottom">(N=75)</td> </tr> <tr ID="id_e27fea26-1554-4981-8da2-5bdab4b56e17"> <td align="left" valign="bottom"> Adverse Reactions</td> <td align="center" valign="bottom">%</td> <td align="center" valign="bottom">%</td> <td align="center" valign="bottom">%</td> <td align="center" valign="bottom">%</td> <td align="center" valign="bottom">%</td> </tr> <tr ID="id_6ea6f92b-7e8e-45b6-8a1c-c7d299d5e74f"> <td align="left" valign="bottom">Genitourinary</td> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> <td align="left" valign="bottom"/> </tr> <tr ID="id_f7246a6b-3d2a-433a-9ed6-b52d898c3836"> <td align="left" valign="bottom"> Renal Dysfunction</td> <td align="center" valign="bottom">32</td> <td align="center" valign="bottom">6</td> <td align="center" valign="bottom">25</td> <td align="center" valign="bottom">38</td> <td align="center" valign="bottom">37</td> </tr> <tr ID="id_1c9cfce4-db25-4118-a9ef-620ab4bb3f87"> <td align="left" valign="bottom">Cardiovascular</td> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_0687edbb-c023-4f6d-800b-ee81b6fa23f2"> <td align="left" valign="bottom"> Hypertension</td> <td align="center" valign="bottom">26</td> <td align="center" valign="bottom">18</td> <td align="center" valign="bottom">13</td> <td align="center" valign="bottom">53</td> <td align="center" valign="bottom">27</td> </tr> <tr ID="id_0a8d80ef-10e7-47e9-8f2e-c0852e8aa49c"> <td align="left" valign="bottom"> Cramps</td> <td align="center" valign="bottom">4</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">2</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">0</td> </tr> <tr ID="id_1d131bb1-302b-49ac-adf3-03fc0f3d4591"> <td align="left" valign="bottom">Skin</td> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_34529311-4206-4fe3-9e90-9c95b5437152"> <td align="left" valign="bottom"> Hirsutism</td> <td align="center" valign="bottom">21</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">21</td> <td align="center" valign="bottom">28</td> <td align="center" valign="bottom">45</td> </tr> <tr ID="id_f578130e-77d1-46b9-9513-976f14e96a36"> <td align="left" valign="bottom"> Acne</td> <td align="center" valign="bottom">6</td> <td align="center" valign="bottom">8</td> <td align="center" valign="bottom">2</td> <td align="center" valign="bottom">2</td> <td align="center" valign="bottom">1</td> </tr> <tr ID="id_0bb04e30-7159-49db-9d5c-3df2eaaff51d"> <td align="left" valign="bottom">Central Nervous System</td> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_1986cebd-9038-48c3-950f-51f7d424b723"> <td align="left" valign="bottom"> Tremor</td> <td align="center" valign="bottom">12</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">21</td> <td align="center" valign="bottom">31</td> <td align="center" valign="bottom">55</td> </tr> <tr ID="id_d8d422b2-7981-48fb-a40a-4a7f257c064e"> <td align="left" valign="bottom"> Convulsions</td> <td align="center" valign="bottom">3</td> <td align="center" valign="bottom">1</td> <td align="center" valign="bottom">1</td> <td align="center" valign="bottom">4</td> <td align="center" valign="bottom">5</td> </tr> <tr ID="id_0990fbe8-7b46-4de1-a0d3-64b811c31fcc"> <td align="left" valign="bottom"> Headache</td> <td align="center" valign="bottom">2</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">2</td> <td align="center" valign="bottom">15</td> <td align="center" valign="bottom">4</td> </tr> <tr ID="id_fcf3699a-7991-4253-a0f3-494a6042b2ae"> <td align="left" valign="bottom">Gastrointestinal</td> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_0176e202-f9d5-4e3e-ac4b-0ceb035cdf26"> <td align="left" valign="bottom"> Gum Hyperplasia</td> <td align="center" valign="bottom">4</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">9</td> <td align="center" valign="bottom">5</td> <td align="center" valign="bottom">16</td> </tr> <tr ID="id_77eb1530-b34f-401f-bb3a-b21785165ad3"> <td align="left" valign="bottom"> Diarrhea</td> <td align="center" valign="bottom">3</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">3</td> <td align="center" valign="bottom">4</td> <td align="center" valign="bottom">8</td> </tr> <tr ID="id_fd67dd13-9ce4-4da8-8b68-16488f4f9edb"> <td align="left" valign="bottom"> Nausea/Vomiting</td> <td align="center" valign="bottom">2</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">4</td> <td align="center" valign="bottom">10</td> <td align="center" valign="bottom">4</td> </tr> <tr ID="id_6993af79-5088-4955-a8cd-dff7ed421831"> <td align="left" valign="bottom"> Hepatotoxicity</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">4</td> <td align="center" valign="bottom">7</td> <td align="center" valign="bottom">4</td> </tr> <tr ID="id_f15407d6-17c0-4b52-b076-3288307f12e2"> <td align="left" valign="bottom"> Abdominal Discomfort</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">7</td> <td align="center" valign="bottom">0</td> </tr> <tr ID="id_fec2fdc5-bfbd-47ea-9a9f-ba0261118d8e"> <td align="left" valign="bottom">Autonomic Nervous System</td> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_e2d0e443-c85b-4ebc-9942-b8ed4e7195f3"> <td align="left" valign="bottom"> Paresthesia</td> <td align="center" valign="bottom">3</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">1</td> <td align="center" valign="bottom">2</td> <td align="center" valign="bottom">1</td> </tr> <tr ID="id_4453681b-fd48-4a08-bc29-ffb5a525b27d"> <td align="left" valign="bottom"> Flushing</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">4</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">4</td> </tr> <tr ID="id_e2caaf19-040c-44ef-a0d2-d3f7ffb9c19f"> <td align="left" valign="bottom">Hematopoietic</td> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_20f9509b-217f-43b6-b0c5-d12a620b1495"> <td align="left" valign="bottom"> Leukopenia</td> <td align="center" valign="bottom">2</td> <td align="center" valign="bottom">19</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">6</td> <td align="center" valign="bottom">0</td> </tr> <tr ID="id_9e8d845f-1bda-42c7-96fd-8592e687811b"> <td align="left" valign="bottom"> Lymphoma</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">1</td> <td align="center" valign="bottom">6</td> <td align="center" valign="bottom">1</td> </tr> <tr ID="id_f1a13c2e-ebca-48c9-ba01-8f33c874420b"> <td align="left" valign="bottom">Respiratory</td> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_664fc675-09d5-43f6-a603-9c12f31d6143"> <td align="left" valign="bottom"> Sinusitis</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">4</td> <td align="center" valign="bottom">3</td> <td align="center" valign="bottom">7</td> </tr> <tr ID="id_544b6924-dad2-4925-9868-18747da37a0a"> <td align="left" valign="bottom">Miscellaneous</td> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> <td align="center" valign="bottom"/> </tr> <tr ID="id_baf39b43-6ff7-4440-a47b-34f6c7810e29"> <td align="left" valign="bottom"> Gynecomastia</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">&lt; 1</td> <td align="center" valign="bottom">4</td> <td align="center" valign="bottom">3</td> </tr> </tbody> </table>

<table border="none" width="467" ID="id_39e7d354-9503-4c0c-a21c-4bed0882d3e0"> <col width="44.1%"/> <col width="17.1%"/> <col width="16.5%"/> <col width="22.3%"/> <tbody> <tr ID="id_eb5eea9e-84e4-4fee-86e8-c011de337bea"> <td align="center" colspan="4" valign="bottom">Renal Transplant Patients in Whom Therapy Was Discontinued</td> </tr> <tr ID="id_ccda67dd-ebab-4afa-b55f-e6becf8f9118"> <td align="left" valign="bottom"/> <td align="center" colspan="2" valign="bottom">Randomized Patients </td> <td align="center" valign="bottom">All Cyclosporine Patients </td> </tr> <tr ID="id_c668dae9-6983-419c-ba20-0d1257e5b5d7"> <td align="left" valign="bottom"/> <td align="center" valign="bottom">Cyclosporine</td> <td align="center" valign="bottom">Azathioprine</td> <td align="center" valign="bottom"/> </tr> <tr ID="id_92b77989-ecf5-490c-9f38-9185e6a8af25"> <td align="left" valign="bottom"/> <td align="center" valign="bottom">(N=227)</td> <td align="center" valign="bottom">(N=228)</td> <td align="center" valign="bottom">(N=705)</td> </tr> <tr ID="id_036f4ccd-6a5a-4160-99e4-0da6b77be283"> <td align="left" valign="bottom">Reason for Discontinuation</td> <td align="center" valign="bottom">%</td> <td align="center" valign="bottom">%</td> <td align="center" valign="bottom">%</td> </tr> <tr ID="id_9ab65a10-e0f6-423c-b9a6-5849c7b2cf6d"> <td align="left" valign="bottom">Renal Toxicity</td> <td align="center" valign="bottom">5.7</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">5.4</td> </tr> <tr ID="id_31547c8f-6774-4036-b8f2-43e05972a369"> <td align="left" valign="bottom">Infection</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">0.4</td> <td align="center" valign="bottom">0.9</td> </tr> <tr ID="id_7ca0b12d-4bc7-4f39-9c86-640d9b1838bc"> <td align="left" valign="bottom">Lack of Efficacy</td> <td align="center" valign="bottom">2.6</td> <td align="center" valign="bottom">0.9</td> <td align="center" valign="bottom">1.4</td> </tr> <tr ID="id_84569e67-674c-4207-9870-3fe2705e82b4"> <td align="left" valign="bottom">Acute Tubular Necrosis</td> <td align="center" valign="bottom">2.6</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">1.0</td> </tr> <tr ID="id_7358e4e3-02b1-4399-9fc8-4aa6466d8dad"> <td align="left" valign="bottom">Lymphoma/Lymphoproliferative Disease</td> <td align="center" valign="bottom">0.4</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">0.3</td> </tr> <tr ID="id_46320f1d-ac9b-48c7-b28b-b516395531b1"> <td align="left" valign="bottom">Hypertension</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">0.3</td> </tr> <tr ID="id_f8147379-39ff-4fb2-9ef2-351980ea5d18"> <td align="left" valign="bottom">Hematological Abnormalities</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">0.4</td> <td align="center" valign="bottom">0</td> </tr> <tr ID="id_c7ae5883-9daa-4f81-8f3f-2f191e87cde3"> <td align="left" valign="bottom">Other</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">0</td> <td align="center" valign="bottom">0.7</td> </tr> <tr ID="id_d9fbe2c7-c90e-4bbb-a5d5-b15d471cf6ba"> <td align="left" colspan="4" valign="bottom">Cyclosporine was discontinued on a temporary basis and then restarted in 18 additional patients.</td> </tr> </tbody> </table>

<table border="none" width="333" ID="id_d939c7ec-6717-4d72-8288-5f7e53ee58c3"> <col width="37.4%"/> <col width="33.8%"/> <col width="28.9%"/> <tbody> <tr ID="id_57e102cd-cc97-4a0c-9697-cf718269b436"> <td align="center" colspan="3" valign="bottom">Infectious Complications in the Randomized Renal Transplant Patients</td> </tr> <tr ID="id_5acf5604-7600-46b3-abfe-427bb8cc8df7"> <td align="left" valign="bottom"/> <td align="center" valign="bottom"> Cyclosporine Treatment</td> <td align="center" valign="bottom">Standard Treatment*</td> </tr> <tr ID="id_70237226-f7c0-40fe-a710-819ade9e080d"> <td align="left" valign="bottom"/> <td align="center" valign="bottom">(N=227)</td> <td align="center" valign="bottom">(N=228)</td> </tr> <tr ID="id_9b849093-29eb-4a88-aa30-9b104f753c5d"> <td align="left" valign="bottom">Complication</td> <td align="center" valign="bottom">% of Complications</td> <td align="center" valign="bottom">% of Complications</td> </tr> <tr ID="id_c4d9a117-5fbc-4782-8508-af274e56d17b"> <td align="left" valign="bottom">Septicemia</td> <td align="center" valign="bottom">5.3</td> <td align="center" valign="bottom">4.8</td> </tr> <tr ID="id_27c766f8-79e4-4616-bf03-76b6a6d34663"> <td align="left" valign="bottom">Abscesses</td> <td align="center" valign="bottom">4.4</td> <td align="center" valign="bottom">5.3</td> </tr> <tr ID="id_520fee46-8a06-4765-a9a2-79beb9c7a953"> <td align="left" valign="bottom">Systemic Fungal Infection</td> <td align="center" valign="bottom">2.2</td> <td align="center" valign="bottom">3.9</td> </tr> <tr ID="id_2def1699-9f0a-4eea-894c-9c02c3999a70"> <td align="left" valign="bottom">Local Fungal Infection</td> <td align="center" valign="bottom">7.5</td> <td align="center" valign="bottom">9.6</td> </tr> <tr ID="id_8aaeca22-2154-45e5-9a6e-53dd944d8a94"> <td align="left" valign="bottom">Cytomegalovirus</td> <td align="center" valign="bottom">4.8</td> <td align="center" valign="bottom">12.3</td> </tr> <tr ID="id_ca3adad0-286c-492c-8309-0b8501a3605a"> <td align="left" valign="bottom">Other Viral Infections</td> <td align="center" valign="bottom">15.9</td> <td align="center" valign="bottom">18.4</td> </tr> <tr ID="id_190e30d5-12b2-4fe4-8ace-f9cabb262b9d"> <td align="left" valign="bottom">Urinary Tract Infections</td> <td align="center" valign="bottom">21.1</td> <td align="center" valign="bottom">20.2</td> </tr> <tr ID="id_bfe8f6ac-b9c0-4ad0-9e37-c7f34943676a"> <td align="left" valign="bottom">Wound and Skin Infections</td> <td align="center" valign="bottom">7.0</td> <td align="center" valign="bottom">10.1</td> </tr> <tr ID="id_d1afeea6-ea09-4c3e-b7a4-263b3af44139"> <td align="left" valign="bottom">Pneumonia</td> <td align="center" valign="bottom">6.2</td> <td align="center" valign="bottom">9.2</td> </tr> </tbody> </table>