Sandimmune

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.

DOSAGE AND ADMINISTRATION Recommended Dosage for Sandimmune Capsules 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. If it is appropriate to switch from Neoral capsules, MODIFIED, to Sandimmune capsules, increase the frequency of cyclosporine monitoring (the cyclosporine dosage may need to be increased to reach the desired cyclosporine exposure and reduce the risk of insufficient efficacy). If it is appropriate to switch from Sandimmune capsules to Neoral capsules, increase the frequency of cyclosporine monitoring (the cyclosporine dosage may need to be decreased to reach the desired cyclosporine exposure and reduce the risk of cyclosporine-related adverse reactions). The initial oral dose of Sandimmune capsules should be given 4 to 12 hours prior to transplantation as a single dose of 15 mg/kg. Although a daily single dose of 14 to 18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale. There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day. The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day. Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate. See Blood Concentration Monitoring, below . Recommended Dosage of the Sandimmune Capsules in Patients with Renal Impairment Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (see CLINICAL PHARMACOLOGY) . However, due to its nephrotoxic potential (see WARNINGS) , careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated (see WARNINGS and PRECAUTIONS) . Recommended Dosage of the Sandimmune Capsules in Patients with Hepatic Impairment The clearance of cyclosporine may be significantly reduced in severe liver disease patients (see CLINICAL PHARMACOLOGY) . Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (see WARNINGS and PRECAUTIONS) . Recommended Dosage of the Sandimmune Capsules in Pediatric Patients In pediatric usage, the same dose and dosing regimen may be used as in adults although in several studies, children have required and tolerated higher doses than those used in adults. Adjunct therapy with adrenal corticosteroids is recommended. Different tapering dosage schedules of prednisone appear to achieve similar results. A dosage schedule based on the patient’s weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Another center started with an initial dose of 200 mg tapered by 40 mg/day until reaching 20 mg/day. After 2 months at this dose, a further reduction to 10 mg/day was made. Adjustments in dosage of prednisone must be made according to the clinical situation. Sandimmune capsules should be administered on a consistent schedule with regard to time of day and relation to meals. Recommended Dosage for Sandimmune Injection Sandimmune injection is for infusion only. Patients unable to take Sandimmune capsules pre- or postoperatively may be treated with Sandimmune Injection, for intravenous use. Sandimmune injection is administered at 1/3 the oral dosage of Sandimmune capsules. The initial dose of Sandimmune injection should be given 4 to 12 hours prior to transplantation as a single intravenous dose of 5 to 6 mg/kg/day. This daily sin…

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 …

CONTRAINDICATIONS Sandimmune capsules and Sandimmune injection are contraindicated in patients with a hypersensitivity reaction to cyclosporine. Sandimmune injection is also contraindicated in patients with a history of a hypersensitivity reaction to Cremophor ® EL (polyoxyethylated castor oil).

Drug Interactions A. Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) with cyclosporine, particularly in the setting of dehydration, may potentiate renal dysfunction. Caution should be exercised when using other drugs which are known to impair renal function (see WARNINGS, Nephrotoxicity) . Drugs That May Potentiate Renal Dysfunction Antibiotics Antineoplastic Antifungals Anti-Inflammatory Drugs Gastrointestinal Agents Immunosuppressives Other Drugs ciprofloxacin melphalan amphotericin B azapropazon cimetidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) gentamicin ketoconazole colchicine ranitidine methotrexate tobramycin diclofenac trimethoprim with sulfamethoxazole naproxen vancomycin sulindac During the concomitant use of a drug that may exhibit additive or synergistic renal impairment potential with cyclosporine, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, reduction in the dosage of cyclosporine and/or coadministered drug or an alternative treatment should be considered. Cyclosporine is extensively metabolized by CYP 3A isoenzymes, in particular CYP3A4, and is a substrate of the multidrug efflux transporter P-glycoprotein. Various agents are known to either increase or decrease plasma or whole blood concentrations of cyclosporine usually by inhibition or induction of CYP3A4 or P-glycoprotein transporter or both. Compounds that decrease cyclosporine absorption, such as orlistat, should be avoided. Appropriate Sandimmune dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly (see DOSAGE AND ADMINISTRATION, Blood Concentration Monitoring) . 1. Drugs That Increase Cyclosporine Concentrations Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs diltiazem fluconazole azithromycin methylprednisolone allopurinol nicardipine itraconazole clarithromycin amiodarone verapamil ketoconazole erythromycin bromocriptine voriconazole quinupristin/ dalfopristin colchicine danazol imatinib metoclopramide nefazodone oral contraceptives HIV Protease inhibitors The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and thus could potentially increase the concentrations of cyclosporine, however, no formal studies of the interaction are available. Care should be exercised when these drugs are administered concomitantly. Grapefruit Juice Grapefruit and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided. 2. Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations Antibiotics Anticonvulsants Other Drugs / Dietary Supplements nafcillin carbamazepine bosentan St. John’s Wort rifampin oxcarbazepine octreotide phenobarbital orlistat phenytoin sulfinpyrazone terbinafine ticlopidine Bosentan Concomitant use of bosentan (250 to 1000 mg every 12 hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a C min of 200 to 250 ng/mL) for 7 days in healthy subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, C max , and trough concentration of approximately 50%, 30% and 60%, respectively, compared to when cyclosporine was given alone (see also Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents) . Concomitant use of cyclosporine with bosentan should be avoided. Boceprevir Concomitant use of boceprevir (800 mg three times daily for 7 days) and cyclosporine (100 mg single dose) in healthy subjects resulted in increases in the mean AUC and C max of cyclosporine approximate…

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cyclosporine, including Sandimmune, during pregnancy. Encourage women who are taking Sandimmune during pregnancy to enroll in the Transplant Pregnancy Registry International (TPRI) by calling 1-877-955-8677 or visiting https://www.transplantpregnancyregistry.org . Risk Summary Available data from published literature, including the Transplant Pregnancy Registry International, observational cohort studies, case-controlled studies, meta-analysis, case series, and case reports, over decades of use with cyclosporine in pregnancy have not identified a drug associated risk of major birth defects, or miscarriage. Adverse maternal or fetal outcomes, including hypertension, preeclampsia, preterm birth, and low birth weight are increased in patients treated with cyclosporine. However, patients receiving cyclosporine during pregnancy have underlying medical conditions and may be treated with concomitant medications that limit the interpretability of these findings (see Data) . Embryo-fetal developmental (EFD) studies in rats and rabbits with cyclosporine have shown embryo-fetal toxicity at dose levels below the MRHD based on BSA. The alcohol content of Sandimmune should be considered when given to pregnant women (see WARNINGS, Special Excipients) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Available data from the National Transplantation Pregnancy Registry (NTPR) including 622 pregnancies in renal, liver, and heart transplant recipients exposed to cyclosporine during pregnancy found that the overall rate of major birth defects, live birth rates, and miscarriage rates were comparable to the general population. Maternal and fetal adverse outcomes, including the rate of hypertension, preeclampsia, premature births, and low birth weight infants appear to be increased in transplant recipients treated with cyclosporine compared to the general population. However, these patients have underlying medical conditions that confound the above findings. Animal Data Animal studies have shown reproductive toxicity in rats and rabbits. Three EFD studies (two oral and one intravenous) are available in rats. In two EFD studies, pregnant rats were orally administered with cyclosporine either at doses of 10, 17, 30, 100 and 300 mg/kg/day or 4, 10 and 25 mg/kg/day from gestation day (GD) 6 to 15 or from GD 7 to 17, respectively. Maternal toxicity characterized by mortality, clinical signs of toxicity and impaired body weight gain were observed at 30 mg/kg/day and above. Cyclosporine was embryo- and fetotoxic as indicated by increased embryonic mortality and reduced fetal weight together with skeletal retardations in rats at 25 mg/kg/day and above. In addition, ventricular septal defect was observed at 25 mg/kg/day in fetuses. In the first study, the oral no observed effect level (NOEL) for both dams and fetuses was 17 mg/kg/day (0.2 times the MRHD based on BSA). In the other oral study, the NOEL for dams and fetuses were 10 and 4 mg/kg/day (0.13 and 0.05 times the MRHD based on BSA), respectively. In the IV EFD study, rats were administered with 3, 6 and 12 mg/kg/day of cyclosporine from GD 7 to 17. An increase in post implantation loss was observed at 12 mg/kg/day; ventricular septal defect was observed at ≥ 6 mg/kg/day in fetuses. The IV NOEL for dams and fetus were 6 and 3 mg/kg/day (below the MRHD based on BSA), respectively after IV administration. In rabbits, cyclosporine was orally administered at dose levels of 10, 30, 100 or 300 mg/kg/day from GD 6 to 18. At 100 mg/kg/day and…

Nursing Mothers Cyclosporine and its metabolites are present in human milk following oral and intravenous administration. Adverse effects on the breastfed infant have not been reported. There are no data on the effects of the drug on milk production. The alcohol content of Sandimmune should be considered when given to lactating women (see WARNINGS) . Lactating women are encouraged to avoid additional alcohol intake during treatment. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sandimmune and any potential adverse effects on the breastfed infant from Sandimmune or from the underlying maternal condition.

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 Complic…