FDA label 6e2f5b13-80ef-42ff-a944-e542e5b3f837

WARNING Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe cyclosporine. 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 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 Oral Solution, USP has decreased bioavailability in comparison to Neoral ® soft gelatin capsules (cyclosporine capsules, USP) MODIFIED and Neoral ® oral solution (cyclosporine oral solution, USP) MODIFIED. Cyclosporine and Neoral ® (cyclosporine [MODIFIED]) are not bioequivalent and cannot be used interchangeably without physician supervision. The absorption of cyclosporine during chronic administration of oral solution was found to be erratic. It is recommended that patients taking the oral solution over a period of time be monitored at repeated intervals for cyclosporine blood levels and subsequent dose adjustments be made in order to avoid toxicity 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 .) Neoral ® is a registered trademark of Novartis Pharmaceuticals Corporation.

WARNINGS (See boxed WARNINGs ): Cyclosporine, when used in high doses, can cause hepatotoxicity and nephrotoxicity. It is not unusual for serum creatinine and BUN levels to be elevated during cyclosporine therapy. These elevations in renal transplant patients do not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated. Nephrotoxicity has been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation. Mild nephrotoxicity was generally noted 2–3 months after transplant and consisted of an arrest in the fall of the preoperative elevations of BUN and creatinine at a range of 35–45 mg/dL and 2.0–2.5 mg/dL, respectively. These elevations were often responsive to dosage reduction. More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine. Since these events are similar to rejection episodes, care must be taken to differentiate between them. This form of nephrotoxicity is usually responsive to cyclosporine dosage reduction. Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated to one or the other. It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection. Nephrotoxicity vs. Rejection Parameter Nephrotoxicity Rejection History Donor > 50 years old or hypotensive Prolonged kidney preservation Prolonged anastomosis time Concomitant nephrotoxic drugs Antidonor immune response Retransplant patient Clinical Often > 6 weeks postop p < 0.01 Prolonged initial nonfunction (acute tubular necrosis) Often < 4 weeks postop Fever > 37.5°C Weight gain > 0.5 kg Graft swelling and tenderness Decrease in daily urine volume > 500 mL (or 50%) Laboratory CyA serum trough level > 200 ng/mL Gradual rise in Cr ( < 0.15 mg/dL/day) p < 0.05 Cr plateau < 25% above baseline BUN/Cr ≥ 20 CyA serum trough level < 150 ng/mL Rapid rise in Cr ( > 0.3 mg/dL/day) Cr > 25% above baseline BUN/Cr < 20 Biopsy Arteriolopathy (medial hypertrophy , hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, progressive scarring) Endovasculitis p < 0.001 (proliferation , intimal arteritis , necrosis, sclerosis) Tubular atrophy, isometric vacuolization, isolated calcifications Tubulitis with RBC and WBC casts, some irregular vacuolization Minimal edema Interstitial edema and hemorrhage Mild focal infiltrates Diffuse moderate to severe mononuclear infiltrates p < 0.0001 Diffuse interstitial fibrosis, often striped form Glomerulitis (mononuclear cells) Aspiration Cytology CyA deposits in tubular and endothelial cells Fine isometric vacuolization of tubular cells Inflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid cells, and activated T-cells These strongly express HLA-DR antigens Urine Cytology Tubular cells with vacuolization and granularization Degenerative tubular cells, plasma cells, and lymphocyturia > 20% of sediment Manometry Intracapsular pressure < 40 mm Hg Intracapsular pressure > 40 mm Hg Ultra-sonography Unchanged graft cross-sectional area Increase in graft cross-sectional area AP diameter ≥ Transverse diameter Magnetic Resonance Imagery Normal appearance Loss of distinct corticomedullary junction, swelling, image intensity of parachyma approaching that of psoas, loss of hilar fat Radionuclide Scan Normal or generally decreased perfusion Decrease in tubular function ( 131 I-hippuran) > decrease in perfusion ( 99m Tc DTPA) Patchy arterial flow Decrease in perfusion > decrease in tubular function Increased uptake of Indium 111 labeled Platelets or Tc-99m in colloid Therapy Responds to decreased cyclosporine Responds to increased steroids or antilymphocyte globulin A form of chronic progressive cyclosporine-associated nephrotoxicity is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5%–15% of transplant recipients will fail to show a reduction in a rising serum creatinine despite a decrease or discontinuation of cyclosporine therapy. Renal biopsies from these patients will demonstrate an interstitial fibrosis with tubular atrophy. In addition, toxic tubulopathy, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy may be present. Though none of these morphologic changes is entirely specific, a histologic diagnosis of chronic progressive cyclosporine-associated nephrotoxicity requires evidence of these. When considering the development of chronic nephrotoxicity it is noteworthy that several authors have reported an association between the appearance of interstitial fibrosis and higher cumulative doses or persistently high circulating trough levels of cyclosporine. This is particularly true during the first 6 posttransplant months when the dosage tends to be highest and when, in kidney recipients, the organ appears to be most vulnerable to the toxic effects of cyclosporine. Among other contributing factors to the development of interstitial fibrosis in these patients must be included, prolonged perfusion time, warm ischemia time, as well as episodes of acute toxicity, and acute and chronic rejection. The reversibility of interstitial fibrosis and its correlation to renal function have not yet been determined. Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated. In patients with persistent high elevations of BUN and creatinine who are unresponsive to dosage adjustments, consideration should be given to switching to other immunosuppressive therapy. In the event of severe and unremitting rejection, it is preferable to allow the kidney transplant to be rejected and removed rather than increase the cyclosporine dosage to a very high level in an attempt to reverse the rejection. Occasionally patients have developed a syndrome of thrombocytopenia and microangiopathic hemolytic anemia which may result in graft failure. The vasculopathy can occur in the absence of rejection and is accompanied by avid platelet consumption within the graft as demonstrated by Indium 111 labeled platelet studies. Neither the pathogenesis nor the management of this syndrome is clear. Though resolution has occurred after reduction or discontinuation of cyclosporine and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans. (See ADVERSE REACTIONS . ) Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients. Hepatotoxicity has been noted in 4% of cases of renal transplantation, 7% of cases of cardiac transplantation, and 4% of cases of liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine were used and consisted of elevations of hepatic enzymes and bilirubin. The chemistry elevations usually decreased with a reduction in dosage. As in patients receiving other immunosuppressants, those patients receiving cyclosporine are at increased risk for development of lymphomas and other malignancies, particularly those of the skin. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. Because of the danger of oversuppression of the immune system, which can also increase susceptibility to infection, cyclosporine should not be administered with other immunosuppressive agents except adrenal corticosteroids. The efficacy and safety of cyclosporine in combination with other immunosuppressive agents have not been determined. Some malignancies may be fatal. Transplant patients receiving cyclosporine are at increased risk for serious infection with fatal outcome. Latent Viral Infections Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus-associated nephropathy which has been observed in patients receiving immunosuppressants, including cyclosporine. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss. Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy. There have been reports of convulsions in adult and pediatric patients receiving cyclosporine, particularly in combination with high-dose methylprednisolone. Encephalopathy has been described both in postmarketing reports and in the literature. Manifestations include impaired consciousness, convulsions, visual disturbances (including blindness), loss of motor function, movement disorders and psychiatric disturbances. In many cases, changes in the white matter have been detected using imaging techniques and pathologic specimens. Predisposing factors such as hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood concentrations, and graft-versus-host disease have been noted in many but not all of the reported cases. The changes in most cases have been reversible upon discontinuation of cyclosporine, and in some cases, improvement was noted after reduction of dose. It appears that patients receiving liver transplant are more susceptible to encephalopathy than those receiving kidney transplant. Another rare manifestation of cyclosporine-induced neurotoxicity is optic disc edema including papilloedema, with possible visual impairment, secondary to benign intracranial hypertension. Anaphylactic reactions have not been reported with the oral solution which lacks polyoxyethylated castor oil. In fact, patients experiencing anaphylactic reactions have been treated subsequently with the oral solution without incident. Care should be taken in using cyclosporine with nephrotoxic drugs. (See PRECAUTIONS.) Because cyclosporine is not bioequivalent to Neoral ® ( cyclosporine [MODIFIED]), conversion from Neoral ® (cyclosporine [MODIFIED]) to cyclosporine using a 1:1 ratio (mg/kg/day) may result in a lower cyclosporine blood concentration. Conversion from Neoral ® (cyclosporine [MODIFIED]) to cyclosporine should be made with increased blood concentration monitoring to avoid the potential of underdosing

<table ID="ID16" width="73%"> <col width="30%"/> <col width="36%"/> <col width="32%"/> <tbody> <tr> <td colspan="3" valign="top" styleCode=" Toprule" align="center"> <content styleCode="bold"> Nephrotoxicity vs. Rejection</content> </td> </tr> <tr> <td valign="top" styleCode=" Botrule" align="left"> <content styleCode="bold"> Parameter</content> </td> <td valign="top" styleCode=" Botrule" align="left"> <content styleCode="bold"> Nephrotoxicity</content> </td> <td valign="top" styleCode=" Botrule" align="left"> <content styleCode="bold"> Rejection</content> </td> </tr> <tr> <td valign="top" align="left"> History </td> <td valign="top" align="left"> Donor &gt; 50 years old or hypotensive Prolonged kidney preservation Prolonged anastomosis time Concomitant nephrotoxic drugs </td> <td valign="top" align="left"> Antidonor immune response Retransplant patient </td> </tr> <tr> <td valign="top" align="left"> Clinical </td> <td valign="top" align="left"> Often &gt; 6 weeks postop<footnote ID="ID160"> p &lt; 0.01</footnote> Prolonged initial nonfunction (acute tubular necrosis) </td> <td valign="top" align="left"> Often &lt; 4 weeks postop<footnoteRef IDREF="ID160"/> Fever &gt; 37.5&#xB0;C Weight gain &gt; 0.5 kg Graft swelling and tenderness Decrease in daily urine volume &gt; 500 mL (or 50%) </td> </tr> <tr> <td valign="top" align="left"> Laboratory </td> <td valign="top" align="left"> CyA serum trough level &gt; 200 ng/mL Gradual rise in Cr ( &lt; 0.15 mg/dL/day)<footnote ID="ID161"> <sub/>p &lt; 0.05</footnote> Cr plateau &lt; 25% above baseline BUN/Cr &#x2265; 20 </td> <td valign="top" align="left"> CyA serum trough level &lt; 150 ng/mL Rapid rise in Cr ( &gt; 0.3 mg/dL/day)<footnoteRef IDREF="ID161"/> Cr &gt; 25% above baseline BUN/Cr &lt; 20 </td> </tr> <tr> <td valign="top" align="left"> Biopsy </td> <td valign="top" align="left"> Arteriolopathy (medial hypertrophy<footnoteRef IDREF="ID161"/>, hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, progressive scarring) </td> <td valign="top" align="left"> Endovasculitis<footnote ID="ID162"> p &lt; 0.001</footnote>(proliferation<footnoteRef IDREF="ID161"/>, intimal arteritis<footnoteRef IDREF="ID160"/>, necrosis, sclerosis) </td> </tr> <tr> <td valign="top"/> <td valign="top" align="left"> Tubular atrophy, isometric vacuolization, isolated calcifications </td> <td valign="top" align="left"> Tubulitis with RBC<footnoteRef IDREF="ID160"/> and WBC<footnoteRef IDREF="ID160"/>casts, some irregular vacuolization </td> </tr> <tr> <td valign="top"/> <td valign="top" align="left"> Minimal edema </td> <td valign="top" align="left"> Interstitial edema<footnoteRef IDREF="ID162"/> and hemorrhage<footnoteRef IDREF="ID160"/> </td> </tr> <tr> <td valign="top"/> <td valign="top" align="left"> Mild focal infiltrates<footnoteRef IDREF="ID162"/> </td> <td valign="top" align="left"> Diffuse moderate to severe mononuclear infiltrates<footnote ID="ID163"> p &lt; 0.0001</footnote> </td> </tr> <tr> <td valign="top"/> <td valign="top" align="left"> Diffuse interstitial fibrosis, often striped form </td> <td valign="top" align="left"> Glomerulitis (mononuclear cells)<footnoteRef IDREF="ID162"/> </td> </tr> <tr> <td valign="top" align="left"> Aspiration Cytology </td> <td valign="top" align="left"> CyA deposits in tubular and endothelial cells Fine isometric vacuolization of tubular cells </td> <td valign="top" align="left"> Inflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid cells, and activated T-cells These strongly express HLA-DR antigens </td> </tr> <tr> <td valign="top" align="left"> Urine Cytology </td> <td valign="top" align="left"> Tubular cells with vacuolization and granularization </td> <td valign="top" align="left"> Degenerative tubular cells, plasma cells, and lymphocyturia &gt; 20% of sediment </td> </tr> <tr> <td valign="top" align="left"> Manometry </td> <td valign="top" align="left"> Intracapsular pressure &lt; 40 mm Hg<footnoteRef IDREF="ID160"/> </td> <td valign="top" align="left"> Intracapsular pressure &gt; 40 mm Hg<footnoteRef IDREF="ID160"/> </td> </tr> <tr> <td valign="top" align="left"> Ultra-sonography </td> <td valign="top" align="left"> Unchanged graft cross-sectional area </td> <td valign="top" align="left"> Increase in graft cross-sectional area AP diameter &#x2265; Transverse diameter </td> </tr> <tr> <td valign="top" align="left"> Magnetic Resonance Imagery </td> <td valign="top" align="left"> Normal appearance </td> <td valign="top" align="left"> Loss of distinct corticomedullary junction, swelling, image intensity of parachyma approaching that of psoas, loss of hilar fat </td> </tr> <tr> <td valign="top" align="left"> Radionuclide Scan </td> <td valign="top" align="left"> Normal or generally decreased perfusion Decrease in tubular function (¹³¹ I-hippuran) &gt; decrease in perfusion (^99m Tc DTPA) </td> <td valign="top" align="left"> Patchy arterial flow Decrease in perfusion &gt; decrease in tubular function Increased uptake of Indium 111 labeled Platelets or Tc-99m in colloid </td> </tr> <tr> <td valign="top" align="left"> Therapy </td> <td valign="top" align="left"> Responds to decreased cyclosporine </td> <td valign="top" align="left"> Responds to increased steroids or 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/ Adverse Reactions (N=227) % (N=228) % (N=705) % (N=112) % (N=75) % 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 Reason for Discontinuation Cyclosporine (N=227) % Azathioprine (N=228) % (N=705) % 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. Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine-containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic). Both generalized and localized infections can occur. Pre-existing infections may also be aggravated. Fatal outcomes have been reported. (see WARNINGS ) Infectious Complications in the Randomized Renal Transplant Patients Complication Cyclosporine Treatment (N=227) % of Complications Standard Treatment Some patients also received ALG. (N=228) % 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 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. Postmarketing Experience BK virus associated nephropathy has been observed in patients receiving immunosuppressants, including cyclosporine. This infection is associated with serious outcomes, including deteriorating renal function and renal graft loss (see WARNINGS ).

<table ID="ID55" width="86%"> <col width="25%"/> <col width="15%"/> <col width="11%"/> <col width="16%"/> <col width="15%"/> <col width="14%"/> <tbody> <tr> <td rowspan="2" valign="top" styleCode=" Toprule"/> <td colspan="2" valign="top" styleCode=" Toprule" align="center"> <content styleCode="bold"> Randomized Kidney Patients</content> </td> <td colspan="3" valign="top" styleCode=" Toprule" align="center"> <content styleCode="bold"> All Cyclosporine Patients</content> </td> </tr> <tr> <td valign="top" align="center"> <content styleCode="bold"> Cyclosporine</content> </td> <td valign="top" align="center"> <content styleCode="bold"> Azathioprine</content> </td> <td valign="top" align="center"> <content styleCode="bold"> Kidney</content> </td> <td valign="top" align="center"> <content styleCode="bold"> Heart</content> </td> <td valign="top" align="center"> <content styleCode="bold"> Liver</content> </td> </tr> <tr> <td valign="top" styleCode=" Botrule" align="left"> <content styleCode="bold"> Body System/</content> <content styleCode="bold"> Adverse Reactions</content> </td> <td valign="top" styleCode=" Botrule" align="center"> <content styleCode="bold"> (N=227)</content> <content styleCode="bold"> %</content> </td> <td valign="top" styleCode=" Botrule" align="center"> <content styleCode="bold"> (N=228)</content> <content styleCode="bold"> %</content> </td> <td valign="top" styleCode=" Botrule" align="center"> <content styleCode="bold"> (N=705)</content> <content styleCode="bold"> %</content> </td> <td valign="top" styleCode=" Botrule" align="center"> <content styleCode="bold"> (N=112)</content> <content styleCode="bold"> %</content> </td> <td valign="top" styleCode=" Botrule" align="center"> <content styleCode="bold"> (N=75)</content> <content styleCode="bold"> %</content> </td> </tr> <tr> <td valign="top" align="left"> <content styleCode="bold"> Genitourinary</content> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td align="left"> Renal Dysfunction </td> <td align="center"> 32 </td> <td align="center"> 6 </td> <td align="center"> 25 </td> <td align="center"> 38 </td> <td align="center"> 37 </td> </tr> <tr> <td valign="top" align="left"> <content styleCode="bold"> Cardiovascular</content> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td align="left"> Hypertension </td> <td align="center"> 26 </td> <td align="center"> 18 </td> <td align="center"> 13 </td> <td align="center"> 53 </td> <td align="center"> 27 </td> </tr> <tr> <td align="left"> Cramps </td> <td align="center"> 4 </td> <td align="center"> &lt; 1 </td> <td align="center"> 2 </td> <td align="center"> &lt; 1 </td> <td align="center"> 0 </td> </tr> <tr> <td valign="top" align="left"> <content styleCode="bold"> Skin</content> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td align="left"> Hirsutism </td> <td align="center"> 21 </td> <td align="center"> &lt; 1 </td> <td align="center"> 21 </td> <td align="center"> 28 </td> <td align="center"> 45 </td> </tr> <tr> <td align="left"> Acne </td> <td align="center"> 6 </td> <td align="center"> 8 </td> <td align="center"> 2 </td> <td align="center"> 2 </td> <td align="center"> 1 </td> </tr> <tr> <td valign="top" align="left"> <content styleCode="bold"> Central Nervous System</content> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td align="left"> Tremor </td> <td align="center"> 12 </td> <td align="center"> 0 </td> <td align="center"> 21 </td> <td align="center"> 31 </td> <td align="center"> 55 </td> </tr> <tr> <td align="left"> Convulsions </td> <td align="center"> 3 </td> <td align="center"> 1 </td> <td align="center"> 1 </td> <td align="center"> 4 </td> <td align="center"> 5 </td> </tr> <tr> <td align="left"> Headache </td> <td align="center"> 2 </td> <td align="center"> &lt; 1 </td> <td align="center"> 2 </td> <td align="center"> 15 </td> <td align="center"> 4 </td> </tr> <tr> <td valign="top" align="left"> <content styleCode="bold"> Gastrointestinal</content> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td align="left"> Gum Hyperplasia </td> <td align="center"> 4 </td> <td align="center"> 0 </td> <td align="center"> 9 </td> <td align="center"> 5 </td> <td align="center"> 16 </td> </tr> <tr> <td align="left"> Diarrhea </td> <td align="center"> 3 </td> <td align="center"> &lt; 1 </td> <td align="center"> 3 </td> <td align="center"> 4 </td> <td align="center"> 8 </td> </tr> <tr> <td align="left"> Nausea/Vomiting </td> <td align="center"> 2 </td> <td align="center"> &lt; 1 </td> <td align="center"> 4 </td> <td align="center"> 10 </td> <td align="center"> 4 </td> </tr> <tr> <td align="left"> Hepatotoxicity </td> <td align="center"> &lt; 1 </td> <td align="center"> &lt; 1 </td> <td align="center"> 4 </td> <td align="center"> 7 </td> <td align="center"> 4 </td> </tr> <tr> <td align="left"> Abdominal Discomfort </td> <td align="center"> &lt; 1 </td> <td align="center"> 0 </td> <td align="center"> &lt; 1 </td> <td align="center"> 7 </td> <td align="center"> 0 </td> </tr> <tr> <td valign="top" align="left"> <content styleCode="bold"> Autonomic Nervous System</content> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td align="left"> Paresthesia </td> <td align="center"> 3 </td> <td align="center"> 0 </td> <td align="center"> 1 </td> <td align="center"> 2 </td> <td align="center"> 1 </td> </tr> <tr> <td align="left"> Flushing </td> <td align="center"> &lt; 1 </td> <td align="center"> 0 </td> <td align="center"> 4 </td> <td align="center"> 0 </td> <td align="center"> 4 </td> </tr> <tr> <td valign="top" align="left"> <content styleCode="bold"> Hematopoietic</content> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td align="left"> Leukopenia </td> <td align="center"> 2 </td> <td align="center"> 19 </td> <td align="center"> &lt; 1 </td> <td align="center"> 6 </td> <td align="center"> 0 </td> </tr> <tr> <td align="left"> Lymphoma </td> <td align="center"> &lt; 1 </td> <td align="center"> 0 </td> <td align="center"> 1 </td> <td align="center"> 6 </td> <td align="center"> 1 </td> </tr> <tr> <td valign="top" align="left"> <content styleCode="bold"> Respiratory</content> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td align="left"> Sinusitis </td> <td align="center"> &lt; 1 </td> <td align="center"> 0 </td> <td align="center"> 4 </td> <td align="center"> 3 </td> <td align="center"> 7 </td> </tr> <tr> <td valign="top" align="left"> <content styleCode="bold"> Miscellaneous</content> </td> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> <td valign="top"/> </tr> <tr> <td align="left"> Gynecomastia </td> <td align="center"> &lt; 1 </td> <td align="center"> 0 </td> <td align="center"> &lt; 1 </td> <td align="center"> 4 </td> <td align="center"> 3 </td> </tr> </tbody> </table>

<table ID="ID57" width="679"> <caption> Renal Transplant Patients in Whom Therapy Was Discontinued </caption> <col width="226"/> <col width="123"/> <col width="123"/> <col width="207"/> <tbody> <tr> <td valign="bottom" styleCode=" Toprule" align="left"> </td> <td colspan="2" valign="top" styleCode=" Toprule" align="center"> <content styleCode="bold"> Randomized Patients</content> </td> <td valign="bottom" styleCode=" Toprule" align="center"> <content styleCode="bold"> All Cyclosporine Patients</content> </td> </tr> <tr> <td valign="bottom" styleCode=" Botrule" align="left"> <content styleCode="bold"> Reason for Discontinuation</content> </td> <td styleCode=" Botrule" align="center"> <content styleCode="bold"> Cyclosporine</content> <content styleCode="bold"> (N=227)</content> <content styleCode="bold"> %</content> </td> <td styleCode=" Botrule" align="center"> <content styleCode="bold"> Azathioprine</content> <content styleCode="bold"> (N=228)</content> <content styleCode="bold"> %</content> </td> <td valign="bottom" styleCode=" Botrule" align="center"> <content styleCode="bold"> (N=705)</content> <content styleCode="bold"> %</content> </td> </tr> <tr> <td align="left"> Renal Toxicity </td> <td align="center"> 5.7 </td> <td align="center"> 0 </td> <td align="center"> 5.4 </td> </tr> <tr> <td align="left"> Infection </td> <td align="center"> 0 </td> <td align="center"> 0.4 </td> <td align="center"> 0.9 </td> </tr> <tr> <td align="left"> Lack of Efficacy </td> <td align="center"> 2.6 </td> <td align="center"> 0.9 </td> <td align="center"> 1.4 </td> </tr> <tr> <td align="left"> Acute Tubular Necrosis </td> <td align="center"> 2.6 </td> <td align="center"> 0 </td> <td align="center"> 1.0 </td> </tr> <tr> <td align="left"> Lymphoma/Lymphoproliferative Disease </td> <td valign="bottom" align="center"> 0.4 </td> <td valign="bottom" align="center"> 0 </td> <td valign="bottom" align="center"> 0.3 </td> </tr> <tr> <td align="left"> Hypertension </td> <td align="center"> 0 </td> <td align="center"> 0 </td> <td align="center"> 0.3 </td> </tr> <tr> <td align="left"> Hematological Abnormalities </td> <td align="center"> 0 </td> <td align="center"> 0.4 </td> <td align="center"> 0 </td> </tr> <tr> <td align="left"> Other </td> <td align="center"> 0 </td> <td align="center"> 0 </td> <td align="center"> 0.7 </td> </tr> </tbody> </table>

<table ID="ID59" width="639"> <caption> Infectious Complications in the Randomized Renal Transplant Patients </caption> <col width="213"/> <col width="213"/> <col width="213"/> <tbody> <tr> <td valign="bottom" styleCode=" Toprule Botrule" align="left"> <content styleCode="bold"> Complication</content> </td> <td valign="top" styleCode=" Toprule Botrule" align="center"> <content styleCode="bold"> Cyclosporine Treatment</content> <content styleCode="bold"> (N=227)</content> <content styleCode="bold"> % of Complications</content> </td> <td valign="top" styleCode=" Toprule Botrule" align="center"> <content styleCode="bold"> Standard Treatment<footnote ID="ID590"> Some patients also received ALG.</footnote> </content> <content styleCode="bold"> (N=228)</content> <content styleCode="bold"> % of Complications</content> </td> </tr> <tr> <td align="left"> Septicemia </td> <td align="center"> 5.3 </td> <td align="center"> 4.8 </td> </tr> <tr> <td align="left"> Abscesses </td> <td align="center"> 4.4 </td> <td align="center"> 5.3 </td> </tr> <tr> <td align="left"> Systemic Fungal Infection </td> <td align="center"> 2.2 </td> <td align="center"> 3.9 </td> </tr> <tr> <td align="left"> Local Fungal Infection </td> <td align="center"> 7.5 </td> <td align="center"> 9.6 </td> </tr> <tr> <td align="left"> Cytomegalovirus </td> <td align="center"> 4.8 </td> <td align="center"> 12.3 </td> </tr> <tr> <td align="left"> Other Viral Infections </td> <td align="center"> 15.9 </td> <td align="center"> 18.4 </td> </tr> <tr> <td align="left"> Urinary Tract Infections </td> <td align="center"> 21.1 </td> <td align="center"> 20.2 </td> </tr> <tr> <td align="left"> Wound and Skin Infections </td> <td align="center"> 7.0 </td> <td align="center"> 10.1 </td> </tr> <tr> <td align="left"> Pneumonia </td> <td align="center"> 6.2 </td> <td align="center"> 9.2 </td> </tr> </tbody> </table>